Mobile genetics and forms of heritable changes in eukaryotes

Mobile genetics and forms of heritable changes in eukaryotes

The real insight in the eukaryotic genome means knowledge of the structure of genetic elements, the character of dynamic links between them and some holistic features of the system. The structure of the eukaryotic genome can be naturally subdivided on two classes of elements: an obligatory and facul...

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Datum:1995
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Veröffentlicht: Інститут молекулярної біології і генетики НАН України 1995
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Zitieren:Mobile genetics and forms of heritable changes in eukaryotes / M. Golubovsky // Биополимеры и клетка. — 1995. — Т. 11, № 2. — С. 29-38. — Бібліогр.: 33 назв. — англ.

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spelling irk-123456789-1556692019-06-18T01:27:49Z Mobile genetics and forms of heritable changes in eukaryotes Golubovsky, M. The real insight in the eukaryotic genome means knowledge of the structure of genetic elements, the character of dynamic links between them and some holistic features of the system. The structure of the eukaryotic genome can be naturally subdivided on two classes of elements: an obligatory and facultative ones. Accordingly, we need to discriminate between two different forms of heritable changes – mutations and variations. Mutations correspond to all changes with genes. Variations are various kinds of changes in the populations of genomic facultative elements. Variations may be directed and connected with multiple site specific alterations. The spontaneous mutation process in nature is mediated by the system of facultative elements. Their activation in nature induces sudden mutation outbursts, appearance of new genetic constructions and site specific rearrangements. Facultative elements are the first to react on environmental challenge. Variations can be presented as an operational memory of the genome. Between obligatory and facultative elements there is constant flow. The behavior of transposons in the eukaryotic genome may be model for the adequate description of epigenic inheritance. There is logic and real necessity to use the epigene concept for describing of elementary units of epigenetic inheritance. Реальне розуміння еукаріотичного геному означає знання структури генетичних еле­ментів, характеру динамічного зв'язку між ними і філософії цілосності системи. Струк­тура еукаріотичного ігеному може бути підрозділеною на два коміпоненти: облігатний і факультативний. Відповідно до цього ми повинні розрізняти дві форми спадкової мінливості – мутаційну і варіаційну. Мутації пов'язані з. усіма змінами в генах. Ва­ріації є різними видами змін у популяціях факультативних елементів геному. Варіації можуть бути визначеними і .пов'язаними з багатьма сайт-специфічними змінами. Спон­танний мутаційний процес у природі обумовлений системою факультативних елементів їх активація у природі індукує раптові мутаційні «вибухи», появу нових генетичяих конструкцій і сайт-специфічних перебудов. Факультативні елементи першими реагують на зміни навколишнього середовища. Варіації можуть бути представлені керуючою па­м'яттю геному. Між облігатними і факультативними елементами спостерігається по­стійна взаємодія. Поведінку транспозонів в еукаріотичному геномі можна взяти за модель для адекватного опису епігенетичної спадковості. Використання концепції епігена є логічною і реальною необхідністю для характеристики елементарних одиниць епігенетичної спадковості. Реальное понимание эукариотического генома означает знание структуры генетических элементов, характера динамической связи между ними и философии целостности системы. Структура эукариотического генома может быть подразделена на два компонента: облигатный и факультативный. Соответственно этому мы должны различать две формы наследственной изменчивости – мутационную и вариационную. Мутации связаны со всеми изменениями в генах. Вариации являются различными видами изменений в популяциях факультативных элементов генома. Вариации могут быть определенными и связаны с многочисленными сайт- специфическими изменениями. Спонтанный мутационный процесс в природе обусловлен системой факультативных элементов. Их активация в природе индуцирует внезапные мутационные -взрывы», появление новых генетических конструкций и сайт-специфических перестроек. Факультативные элементы первыми реагируют на изменения окружающей среды. Вариации могут быть представлены управляющей памятью генома. Между облигатными и факультативными элементами имеется постоянное взаимодействие. Поведение транспозоиов в эукариотическом геноме может быть моделью для адекватного описания эпигенетической наследственности. Использование концепции эпигена является логической и реальной необходимостью для характеристики элементарных единиц эпигенетической наследственности. 1995 Article Mobile genetics and forms of heritable changes in eukaryotes / M. Golubovsky // Биополимеры и клетка. — 1995. — Т. 11, № 2. — С. 29-38. — Бібліогр.: 33 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.0003DD http://dspace.nbuv.gov.ua/handle/123456789/155669 575.17 en Биополимеры и клетка Інститут молекулярної біології і генетики НАН України
institution Digital Library of Periodicals of National Academy of Sciences of Ukraine
collection DSpace DC
language English
description The real insight in the eukaryotic genome means knowledge of the structure of genetic elements, the character of dynamic links between them and some holistic features of the system. The structure of the eukaryotic genome can be naturally subdivided on two classes of elements: an obligatory and facultative ones. Accordingly, we need to discriminate between two different forms of heritable changes – mutations and variations. Mutations correspond to all changes with genes. Variations are various kinds of changes in the populations of genomic facultative elements. Variations may be directed and connected with multiple site specific alterations. The spontaneous mutation process in nature is mediated by the system of facultative elements. Their activation in nature induces sudden mutation outbursts, appearance of new genetic constructions and site specific rearrangements. Facultative elements are the first to react on environmental challenge. Variations can be presented as an operational memory of the genome. Between obligatory and facultative elements there is constant flow. The behavior of transposons in the eukaryotic genome may be model for the adequate description of epigenic inheritance. There is logic and real necessity to use the epigene concept for describing of elementary units of epigenetic inheritance.
format Article
author Golubovsky, M.
spellingShingle Golubovsky, M.
Mobile genetics and forms of heritable changes in eukaryotes
Биополимеры и клетка
author_facet Golubovsky, M.
author_sort Golubovsky, M.
title Mobile genetics and forms of heritable changes in eukaryotes
title_short Mobile genetics and forms of heritable changes in eukaryotes
title_full Mobile genetics and forms of heritable changes in eukaryotes
title_fullStr Mobile genetics and forms of heritable changes in eukaryotes
title_full_unstemmed Mobile genetics and forms of heritable changes in eukaryotes
title_sort mobile genetics and forms of heritable changes in eukaryotes
publisher Інститут молекулярної біології і генетики НАН України
publishDate 1995
url http://dspace.nbuv.gov.ua/handle/123456789/155669
citation_txt Mobile genetics and forms of heritable changes in eukaryotes / M. Golubovsky // Биополимеры и клетка. — 1995. — Т. 11, № 2. — С. 29-38. — Бібліогр.: 33 назв. — англ.
series Биополимеры и клетка
work_keys_str_mv AT golubovskym mobilegeneticsandformsofheritablechangesineukaryotes
first_indexed 2025-07-14T07:51:38Z
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fulltext UDC 575.17 Michael Golubovsky MOBILE GENETICS AND FORMS OF HERITABLE CHANGES IN EUKARYOTES The real insight in the eukaryotic genome means knowledge of the structure of genetic elements, the character of dynamic links between them and some holistic features of the system. The structure of the eukaryotic genome can be naturally subdivided on two classes of elements: an obligatory and facultative ones. Accordingly, we need to dis­ criminate between two different forms of heritable changes — mutations and variations. Mutations correspond to all changes with genes. Variations are various kinds of chan­ ges in the populations of genomic facultative elements. Variations may be directed and connected with multiple site specific alterations. The spontaneous mutation process in nature is mediated by the system of facultative elements. Their activation in nature induces sudden mutation outbursts, appearance of new genetic constructions and site specific rearrangements. Facultative elements are the first to react on environmental challenge. Variations can be presented as an operational memory of the genome. Bet­ ween obligatory and facultative elements there is constant flow. The behavior of tran- sposons in the eukaryotic genome may be model for the adequate description of epigenic inheritance. There is logic and real necessity to use the epigene concept for describing of elementary units of epigenetic inheritance. In this paper I try to present a general approach to the description of heritable alterations in eukaryotes. This task seems important. «Mobile» genetics in many aspects contradicts classical genetics on which the current theory of evolution is based. An adequate description needs to take into account the complexity of the structure of the cell hereditary system. Inheritance can be consi­ dered as the cell's property to provide transmission in a series of gene­ rations all the specific structural and functional traits and specific cha­ racter of ontogenesis. We will use word genome in a broad sense as an equivalent of the whole cell genetic system which determines individual heritable differences. Such a meaning corresponds to the final words of the classical paper about genetic regulation that «the genome contains not only a series of blue-prints, but a coordinate programme of protein synthesis and the means of controlling its execution» [1]. Mutations in the framework of traditional genetics implicit any chan­ ges of molecular structure of genes, their position and number. But do the mutations in this sense embrace all possible hereditary alterations? The answer is no. Mobile genome: obligatory and fecultative elements. The birth of mobile genetics is dated in the earlier 1950s with a series of publications by Barbara McClintock and the A. Lwoff, F. Jacob and E. Wollman from Pasteur Institute. McClintock concluded that the mutant condition may depend on the action of controlling mobile elements able to be inserted in various loci. They may be present or absent in the genome. The diffi­ culty to connect controlling elements with definite DNA structures in­ creased the mystery of McClintock's conclusions. However, the principal support of her ideas came from studies of other facultative elements: episomes and lambda phages in all their in­ carnations. The lysogeny model was published by A. Lwoff in 1953. As this event were into history we can conclude that its impact on the pro­ gression of genetics together with subsequent analysis of episomes by '£< MICHAEL GOLUBOVSKV, 1995 • ISSN 0233-7657. БИОПОЛИМЕРЫ И КЛЕТКА. 1995. Т. 11. № 2 оо E. Jacob and E. Wollman appeared to be as essential as the discovery of the DNA double helix in the same year. The virus with all its genetic machinery might be a genomic facultative element. In the integrated state viruses are indistinguishable from a chromosome element with the potential to supply the host cell with new properties. Thus the genome does not have an absolute barrier from invasion by foreign genetic ele­ ments. In the context of this paper I can't resist the temptation to cite the prophetic conclusion made at the beginning of 1960s: «All intermediate categories may be formed bet­ ween the viruses (extrinsic, in- fectious, plasmids) and the nor­ mal genetic determinants of a cell (intrinsic, noninfectious, and integrated). Between heredity and. infection, between cellular patho­ logy and cellular physiology* between nuclear and cytoplasmic heredity, the episomes, as studied Fig. 1. Main potential ways of intercon- versions between obligatory and faculta­ tive elements of the genome. Arrows in­ dicate directions of transitions. It is shown that aspects of facultativness con­ cerns also behavior of obligate genes. Exogenous retroviruses can be mutatio- nally transformed to plasmids and trans- posons and vice versa. Other facultative elements are shown on the fig. 2 man, regarded these considerations as main contribution of bacterial ge­ netics. In fact, episome studies appeared to be crucial for the develop­ ment of the new mobile genetics with discovery a whole kingdom of fa­ cultative elements. The eukaryotes in their essence are multigenomic symbiotic con­ structions. But apart from self-reproducing organelles the structural ele­ ments of the genome may be naturally subdivided on two subsystems or parts: the OBLIGATORY ELEMENTS and the FACULTATIVE ones or OE and FE [3]. The chromosomal genetic loci are only the skeleton of the genome. The subsystem of FE includes the hierarchy of intra and extrachromoso- mal elements varying from highly repeated and satellite DNA, to trans- posons, pseudogenes and retrotranscripts, amplicons, plasmids, additio­ nal chromosomes and various endosymbionts. The FE may be defined operationally by two criteria: [1] they can be present or absent, and when present their number and topography vary in different cells, tissu­ es, individuals; [2] their intrinsic properties promote to deviations in the character of basic informational processes: replication, transcription, translation and segregation. For instance, highly repeated sequencies are characterized by frequent under or overreplication, they usually are not transcribed; plasmids and B-chromosome do not segregate regularly, etc. Absence of linkage of DNA content in the haploid genome with ta- xonomic status and frequent cases of its drastic differences in closely related species was called as «C-paradox». The word paradox was given due to the evident violation of some basic implicit postulates of classical genetics: (a) all genetic material of chromosomes consists of genes, all DNA has an informational function; (b) the list of genes with their al- 30 ISSN 0233-7657. БИОПОЛИМЕРЫ И КЛЕТКА. 1995. Т. П. № 2 leles correspond to genotypes. However, a lot of structural aspects of eukaryotic genome appeared to be paradoxal (Fig. 1): mosaic structure of genes, programmed ontogenetic rearrangements, ability of many seg­ ments to exist both in chromosomal and plasmid states, the abundance of transposons in their different incarnations and the ubiquitous presence of cytobionts. Nearly 50 families of mobile elements (ME) are described in Droso- phila. They comprise up to 12 % of the haploid DNA content. The mam­ malian genome contains up to 50 000 dispersed copies of retroposon LINE near by 6500 base long. Short Alu mobile element family has about 300 000 dispersed copies. In fact, each individual has his own pattern of number and topography of mobile elements. Intracellular symbionts (viruses, bacteria, protozoa) need also to be viewed as FE of the genome. They may confer on the host cell impor­ tant new properties especially in physiology and mode of reproduction. The behavior of rhabdovirus sigma in Drosophila is one of the best stu­ died examples [4]. The single-stranded RNA virus is non-contagious. But it is stabely transmitted maternally through egg cytoplasm and ma­ kes flies sensitive to C02. Each oogonia of stabilized sensitive females contains 10—40 virus particles and mature oocytes contain about 106 ones. This physiological trait is inherited cytoplasmically and its expres­ sion depends on the concentration of the intracellular viral population. Males of stabilized line transmit sensitivity only sporadically. Some Dro­ sophila stocks are immune to virus infection and some sigma mutants can overcome this immunity. The striking analogy of Drosophila heredi­ tary sensitivity to C02 with the behavior of a phage-bacteria system was noticed long before the rhabdovirus sigma was actually isolated [2]. The general approach needs to use the term «horizontal transfer» to all rela­ tively stable presence in the genome various facultative cytobionts. Thus it is became clear that in nature such transfers are regular events. It should be stressed that aspects of facultativeness concern also ob­ ligatory genes (Fig. 1, upper lines). Introns in some sense may be viewed as facultative intragene elements. As they are spliced they have the ca­ pacity to «absorb» different kinds of inserts without any apparent con­ sequences on normal gene function. Many genes can undergo an alter­ native splicing depending on developmental stage and tissues. Faculta­ tive translation is also described. I n t e г с о n v e r s і о n s in t h e s u b s y s t e m s of OE a n d FE . The prophetic scheme titled as «possible variations of episomes» [2] predicted continuous gradation in the behaviour and properties of FE. In fact, the be stabilized as duplicated gene copies. These events may be viewed as interconversions in subsystems of the OE and FE. There is constant flux between the obligate and facultative subsystems. Mutations and variations. The two structural subsystems of the ge­ nome exhibit different characteristics of heritable alterations. Mutation, in the classical sense, connected mainly with alterations of OE, i. e. chan­ ges in the structure, position and number of genes. (In a more general sense mutations implicit any changes in linear structure of genetic ele­ ments). But FE exist in the genome as populations of informational mac- romolecules. The character of their alterations and their response to the action of external factors is quite different in comparison with OE. To describe the various heritable alterations in the subsystem of FE, I have suggested [8] the term VARIATION firstly used by F. Jacob and E. Woll- man for episome behaviour [2]. Recently P. Foster after studies on an adaptive mutation problem offered to use the term «variant» «to distin­ guish potentially transient changes in the cell's informational macromo- lecules from mutations, which are heritable sequence changes in the DNA» [9]-. Thus there are mutations and mutants and there are variations and variants. Spontaneous mutations according classical theory occur in the progeny of some individuals, by chance, rarely with frequency near 10~6 ISSN 0233-7657. БИОПОЛИМЕРЫ И КЛЕТКА. 1995. Т. 11. № 2 31 for a gene/generation. Mutations can be induced by action of strong en­ vironmental factors (radiation, chemical mutagens et al). Heritable changes of FE occur on the level of intracell population of informational macromolecules. Let's take the well studied phenomenon of hybrid dysgenesis in Drosophila. In the case of P-M dysgenesis in Fl hybrids from paternal P-stock having active P transposons with the fe­ males of M-stock devoid of P-active copies and cytoplasmic repressor of transposition, an outburst of mobility of P-elements occurs. This results in an outburst of insertion mutations and chromosomal rearrangements, ENVIRONMENT Repeated, stDNA Mobile elements Retrotranscripts TATIVE Retroviral DNA •NTS Amplified DNA B-chromosomes Plasmids Cytobionts TIONS Fig. 2. Mutations and variations and character of their occurrence under action of envi­ ronment. Arrows indicate the direction of the links, while their width corresponds to the intencity of their force damages of germinal cells and sterility. There are multiple transpositi­ on events in the separate sensitive cells. The general frequency of chro­ mosomal rearrangements in the Fl progeny of dysgenic crosses may reach fantastic frequencies — more 10%. The chromosomal breaks are ordered and site-specific. They occur at the sites of the original locali­ sations of P-elements. The multisite inversions were observed with the same frequency as simple ones [10]. Thus in the case of variations, on the contrary to mutations, genoty­ pe changes (a) occur simultaneously in many individuals, (b) the alte­ rations are ordered, multisite and site-specific, (c) the positions of ge­ nome rearrangements are predeterminated by the original topography of FE, (d) the activation of FE may be induced by trivial «non-mutagenic» factors as temperature, interline crosses. There is an additional important item. The genotype alteration can occur due to simple changes in the cell topography or relative amounts of two classes OE/FE. Heritable transmission of fly C02 sensitivity in stabilized lines can be cut off by the temperature shock: keeping egg- laying females for about 6 days at 30 °С. Such treatment blocks the re­ production of cytoplasmic sigma virus particles. The all adults flies of C02 sensitive stock became virus-free after one-time treatment and they become heritably tolerant to C02 [4]. This example shows that on the level of FE situations may occur which were prohibited by the tenets of classical genetics, the so called inheritance of traits acquired during ontogenesis [11]-. The character of interactions in the triad ENVIRONMENT-FE-OE is illustrated by the scheme (Fig. 2). In nature spontaneous heritable chan­ ges mainly occur through the response of the FE subsystem which is sen­ sitive both weak and strong environmental influences [12]. Changes in FE represent an operational memory in the structure of the genome. Mu­ tations as changes of OE occur mainly indirectly, by a two step mecha­ nism mediated by the activation of the subsystem of FE. The comparative molecular anatomy of mobile elements both in prokaryotes and eukaryo- tes demonstrated various paths of interconversions of ME from simplest to complex ones: insertion sequences — transposons — plasmids — retro­ viruses and vice versa [5]. 32 ISSN 0233-7657. БИОПОЛИМЕРЫ И КЛЕТКА. 1995. Т. 11. № 2 Let's consider recent evidence on transition of typical chromosomal mobile element gypsy to retroviral infectious condition. The element may be transmitted to gypsy-iree permissive fly stock and incorporated into its germ line when larvae are fed on extracts of infected flies [6]. Such retrovirus-like elements were discovered in yeasts, plants and animals. Retroviruses appear to be universal vector in the ecosystems. The simi­ lar or same retrotranscripts were found in non-related species indicated on regular cases of horizontal transmission. The same is justice for trans- posons-like P in Drosophila Ac and SpM in maize, which use DNA to DNA transposition mechanism [7]. There is no severe barrier between OE and FE parts of genome. The obligatory genes and chromosomal segments may be transformed to the category of FE due to three main processes: amplification, integration into the ME and through production of cytoplasmic RNA intermediates. Conversely, the transition from FE to OE occurs mainly due to inserti­ ons, transposon-induced rearrangements and reverse transcription (Fig. 1). Insertion mutations (transition from FE to OE) may constitute, as in the case of Drosophila, near 70 % of spontaneous visible mutations. Nearly 10—15 % of the chromosomal DNA of mammals consists of pseu- dogenes and retrotranscripts — transitions from OE to FE [8]. Selecti­ on by cytostatic agents in eukaryotes is frequently connected with an amplification of chromosomal segments (amplicons) carrying resistant genes. The amplicons may be located in tandem chromosomal blocks or be transformed into plasmids. In both cases their number and topography vary in different cells and cell lines. Sometimes part of the duplicated genes may insertion mutations as result of activation of ME represent the best example. The behaviour of FE in turn is usually under control of genes. M u t a t i o n p r o c e s s m e d i a t e d by m o b i l e e l e m e n t s i n n a t u r e . I want to confirm the above mentioned conclusions by so­ me inferences from my long-term studies on the spontaneous mutation process in natural populations of D. melanogaster. I selected here only three examples. 1. The puzzling phenomenon of mutation outburst. The concept of mutation rate fluctuation in the life of species was firstly developed by Hugo de Vries in 1901. He also predicted an existence of unstable ge­ netic factors. Both ideas were neglected for decades. However, de Vries appeared to be right in principle. The fluctuations of both general muta­ bility and sudden mutation outburst of definite loci are well documented [13—15]. In 1973—1979 we observed the global outburst of sex-linked gene singed bristle. It was the first time when the series of unstable in­ sertion alleles was extracted from nature [14, 15]. Their mutation rate both in germinal and somatic cells reached in some cases more 20 %•! Multiple allelic transitions occurred in pre-meiotic cells giving cluster of changed garnets in the progeny of a single mating [14, 15]. The sn gene appeared to be preferential target for the now famous P-transposons and for some retrovirus-like ME [16]. Thus we demonstrated that the muta­ tions outbursts in nature are due to an activation of FE. However, the puzzle of phenomenon became unsolved. According to regular observations [13—15] the sn mutations were quite rare in Dro­ sophila populations during decades before 1973. Then unstable alleles of this gene suddenly appeared in many geographically distant popula­ tions. The outburst ended in 1980. Then other gene sharply increased its mutability rate [17]. What may be the origin of such periodical genomic epidemies or «mutation fashions»? The answer may consists of fact that all living species in the eco­ system are continuously interacting with different viruses. Viruses are not only powerful infectious and selective agents. They act also as pe­ culiar mutagenic factor inducing unstable mutations and multisite chro­ mosomal damages due to an activation of intrinsic genomic FE [18—20]. ISSN 0233-7657. БИОПОЛИМЕРЫ И КЛЕТКА. 1995. Т. 11. № 23—4-962 33 Different viral agents cause insertion mutations at different sites. The regular reshuffling of the set of viruses and their genotypes (the latter is well known for the influenza virus in humans) occur in the eco­ systems during the process of parasite-host interaction. So the periodical mutation outbursts and the genomic epidemics may be the indirect re­ sult of periodical ecosystem fluctuations. We need systematic studies on the consequences of viral epidemics on the rate of variations and muta­ tions in human populations [13, 18]. 2. Appearance of new genetic constructions. In the Far East popu­ lation two adjacent genes singed and club wing (clw) appeared to be linked by the copia-like ME. Both genes became simultaneously expres­ sed and mutated. The mutation behaviour of this quite unstable double- gene transposon system was ordered with predicted intralocus and out- locus transpositions [22]. This first demonstration of ME-mediated fu­ sion of separate genes in one system may be viewed as an example of the phenomenon of «natural genetic engineering» [23]. 3. Site-specific insertions and ME-mediated deletions. During syste­ matic study of the genetic load of natural populations we found that lethal alleles of tumor-supressor gene lethal (2) giant larvae or simply Igl (2—0,0) are ubiquitous in D. melanogaster populations (14). One out 20—50 fruit flies in nature was heterozygous on this oncogenic re­ cessive lethal. The -{-/Igl animals had selective advantages in stress con­ ditions in comparison with lethal free + / + flies (14). High Igl muta­ bility appeared to be connected with site specific insertional mutagene­ sis. The Igl locus became «promiscuous» for the specific insertions in the case of the presence in the same chromosome of the MR factor [24]. The same В104 transposon was found inserted in the case of alleles ex­ tracted from the distant populations of Russian and USA [25]. These three examples showed that in nature through subsystem of FE may occur fast directed and massive heritable changes. Epigenetic inheritance and mobile elements. The hereditary memory implies three main aspects: coding, storage are transfer of an informa­ tion. There exist both structural and dynamic modes of coding, storage and transfer of heritable information. As for as of the structure of ge­ nome the coding is based on definite order of DNA sequences and in­ formational transfer on the phenomenon of convariant reduplication. The dynamic modes of inheritance are mediated by protein products of re- gulater genes. The heritable alterations can occur without any changes in DNA text. J. Mono and F. Jacob on the basis of the operon concept firstly presented a theoretical models with two operons connected into circuits. Such cyclic system can switch from one stable state to the other and maintain it in a series of generations. Thus, «transition of state in such systems should very closely mimic true transmissible alteration of the genetic material itself» [26]. Namely such transitions were found by B. McClintock in the case of the SpM mobile controlling element. The dynamic aspects of the genome organisation and functioning were called in the middle of 1950s as epigenetic. The spectrum of phe­ nomena epigenetic inheritance is quite wide from transformation of se­ rotypes in Paramecium up to chromosomal and genomic imprinting. But terminology in this field is not yet stabilized. What is the elementary epigenic system and elementary epigenetic event? For adequate descrip­ tion of epigenetic inheritance it seems quite instrumental to use the con­ cept of an EPIGENE coined by R. Tchuraev [27] and term EPIMUTA- TION suggested by R. Holliday [28]. Epigene represents autoregulatory hereditary unit, genetic system with cyclic links or feedback, having two or more functional states and capable to maintain each state in a series of generations. The simplest one-component epigene is shown in Fig. 3. The feedback may be posi­ tive as in the case of first described autoregulated cl gene which diffe­ rent states rule by the lambda phage behaviour. Autoregulation may be negative as in the case of Tn3 in E. coli [5]. 34 ISSN 0333-7657. БИОПОЛИМЕРЫ И КЛЕТКА. 19%. Т. П. № 2 The transposons P in Drosophila, Ac and SpM in maize are con­ structed as epigenes with positive autoregulation [29—31]. Autoregula- tion by circuit may be based on different mechanisms or levels. In the case of sex determining gene Sxl in Drosophila autoregulation occur on the level of alternative splicing [32]. In the case of P-transposon auto­ regulation involves both alternative splicing and transcription. [29} Ac. F2 Non-mendelian inheritance Fig. 3. An epigene and principal scheme of possible heritable changes in the case of epigenic crosses. In the scheme the positive regulation is shown on the level of trans­ cription. R — gene regulator; Л — structural gene; OP — regulator zone and SpM transposons in maize discovered by B. McClintock are regu­ lated by methylations of up and down promotor sites [30, 31, 33]. The scheme (Fig, 3) shows that in the case of positive autoregula­ tion in cell epiheterozygotes А]/А° where Af-active state of an epigene and A0 inactive one may occur the switching on the epigene from A0 to A1 state. This switching described as epimutation is well documented for an Ac and SpM transposons in maize [30, 31, 33J. Epimutation may oc­ cur both in somatic and germinal cells. In last case the non-mendelian inheritance results in. Even situation is possible with complete absence of F2 segregation (Fig. 3). The transposon SpM in the maize apart from active and complete inactive states may exist in third so called «programmed» state with varying level of inactivity, increased possibility to be trans-activated in epiheterozygotes. The transposon encoded positive autoregulatory gene product can both reactivate an inactive element and promote its deve­ lopmental heritable reprogramming [30, 31 ]!. The authors which had con- ISSN 02G3-7657. БИОПОЛИМЕРЫ И КЛЕТКА. 1995. Т. 11. № 2 З* 35 ducted detailed genetic and molecular analysis of SpM element came to conclusion that to th£ concept' of epimutation «it may be necessary and epivariation» [31]: I cite this conclusion as an important sign of logic and terminological convergence with the approach developed in the paper. • Analysis of S;pM behaviour demonstrated that the epigenetic chan­ g e s ; in the present generation can influence the expression pattern of the transposon in the next generation. Similar phenomenon described in maize in 1960s and titled as paramutation seemed quite peculiar. In the framework of mobile genetics it may be regular. From the point of theo­ ry of inheritance it means violation of one of the basic mendelian prin­ ciple about absence of influence of heterozygous condition on the allelic structure and function in the next generation. Other important point con­ sist of a possibility of an existence in the genome a series of independent epigenes. Thus if we have only 10 epigenes with two states for each one we receive 210 or 1024 different states! Thus cell can select needed stra­ tegy of response on environmental challenge. The cell response is teleo- nomic [12, 26]. Conclusion. The real insight in the eukaryotic genome means know­ ledge of the structure of genetic elements, the character of dynamic links between them and some holistic features of the system. The structure of the eukaryotic genome can be naturally subdivided on two classes of elements: an obligatory and facultative ones. Accordingly, we need to discriminate between two different forms of heritable changes-mutations and variations. Mutations correspond to all changes with genes. Variations are various kinds of changes in the populations of genomic facultative elements. Variations may be directed and connected with rnultiple-site-specific alterations. The spontaneous mu­ tation process in nature is mediated by the system of facultative elements. Their activation in nature induces sudden mutation outbursts, appearan-' ce of new genetic constructions and site-specific rearrangements. Facul­ tative elements are the first to react on environmental challenge. Varia­ tions can be presented as an operational memory of the genome. Between obligatory and facultative elements there is constant flow. The behaviour of iransposons in the eukaryotic genome may be model for the adequate description of epigenetic і inheritance. There is logic and real necessity to use the epigene concept for describing of elementary units of epige- nclic inheritance. The shift of postulates .from classical genetics to current one may be expressed as following. ' Classical genetics ч 1, All newly occurring-hereditary changes are mutations with definite localisation. . . . , ' • . 2. Mutations occur in the progeny of some individuals, rarely, by chance. • " 3. The rale of "mutation process is constant, genes are relatively stable... : • • • • : . • • 4. Epigenetic charges have relation only to development, they are •found mainly in 'some protozoa and in the case of cell-somatic hybrids. '': ' 5. Inheritance оГacquired traits is impossible in the framework of chromosomal theory. 0. Species genoines are genetically closed systems. Current mobile genettcs 1. Mutations are only part of the wide spectrum of heritable alterations; there are variat ionsartd epigenetic changes (epimutations). ! ; ' v 2 .Var ia t ions and •epirriutations may be ordered, directed, program­ med and adaptive. • ••'.•• ' • . 3. In natural- populations' regularly occur explosions of mutability both'4 global and local ones due to an activation of inherent mobile elements. . . ' . - • • • * • • . : • 36 v ISSN 0233-7G57. БИОПОЛИМЕРЫ И КЛЕТКА. 1995. Т. Л. № 2 4. Epigenetic alterations of genome elements are regular events; most transposons are organised as epigenes. 5. Inheritance of ontogenetically induced traits js quite possible in the framework of variations and epimuta-tions. (. , • 6. There is constant intracell and interspecies, flow of genetic elements. Acknowledgements. I am very grateful to Prof. Marc Fellous and Drs Ken McElreavey and Edwige Jakob for support, stimulating discus­ sions, critical reading of manuscript. This article is dedicated to the memory of Andre Lwoff (1902—1994). M. Голубовський МОБІЛЬНА ГЕНЕТИКА І ФОРМИ СПАДКОВОЇ МІНЛИВОСТІ ЕУКАРІОТ Р е з ю м е Реальне розуміння еукаріотичного геному означає знання структури генетичних еле­ ментів, характеру динамічного зв'язку між ними і філософії цілосності системи. Струк­ тура еукаріотичного ігеному може бути підрозділеною на два коміпоненти: облігатниіі і факультативний. Відповідно до цього ми повинні розрізняти дві форми спадкової мінливості — мутаційну і варіаційну. Мутації пов'язані з. усіма змінами в генах. Ва­ ріації є різними видами змін у .популяціях факультативних елементів геному. Варіації можуть бути визначеними і .пов'язаними з багатьма сайт-специфічними змінами. Спон­ танний мутаційний процес у природі обумовлений системою факультативних елементів. їх активація у природі індукує раптові мутаційні «вибухи», появу нових генетичяих конструкцій і сайт-специфічних перебудов. Факультативні елементи першими реагують на зміни навколишнього середовища. 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