Conditional Mutations and New Genes in Drosophila

1. Introduction

A living organism is a biological system working under the control of its genetic system. This genetic system is more compact but more intricate in terms of the information content: in addition, it provides ontogenesis and phylogenesis of the organisms. Gregor Mendel founded the way of knowing for both systems: this is the way “from character to gene”.

The strategy “from character to gene” has emerged to be true. The examples of the inheritance that follows the Mendelian rules are most numerous. The role of chromosomes and later, the role of DNA in heredity have become clear and the DNA code for the construction of proteins of amino acids was discovered. The Mendelian gene, coding for formation of protein, acquired the status of a universal unit of heredity and, therefore, the basic element of a living organism.

However, full-scale human genome sequencing has shown that the protein-coding genes account for only several percent of the entire genome DNA [1]. This means that genetics has so far studied in detail only a small part of the genome, whereas many fundamentally important characters were omitted. Correspondingly, the concept of the protein-coding gene as a universal basic unit of all living is not completely justified and the existence of other categories of genes cannot be excluded. It is a high time to recall the opinion of Kliment Timiryazev, a prominent biologist, on the second discovery of Mendel’s rules. While praising the contribution of Mendel to the understanding of heredity, he warned that the rules for inheritance of alternative characters might appear inapplicable to the inheritance of some other characters of an organism [2].

The traits of intraspecific similarity, which are distinguishable in terms of taxonomy of an organism, are among these other characteristics. Unlike the Mendelian characters varying within a species, they display no variation. The characters of intraspecific similarity are the particular characters that come to mind when speaking about the functions and structures putatively responsible for the part of the DNA molecule that is not associated with protein-coding genes. As a matter of logic, this larger share should accommodate the genes that are responsible for the conserved characters of a living organism, i.e., the characters of species, genus, class, and so on.

This chapter describes examples of non-Mendelian genes. The classical genetic strategy (from character to gene) has been utilized by the authors in this context as well but with an eye towards the putative existence of the DNA regions with the gene properties distinct from those of Mendelian genes. Hereinafter, the Mendelian genes are regarded as the genes (1) responsible for the formation of alternative characters, (2) inherited in accordance with the Mendel’s rules, and (3) coding for proteins.

The detection of a gene according to traditional hybridological procedure consists in of the detection of the variants of the corresponding trait and demonstration of a Mendelian inheritance of the variants. The primary task of the experiments on artificial mutagenesis is to find an individual with a character that distinguishes it from the norm among the offspring of the exposed organism. It is impossible to find the individual carrying a mutation in the gene responsible for a conserved trait since this mutation is a dominant lethal by definition.

As has been theoretically inferred, the lethality of conserved genes is not absolute and the genomes exist where this lethality does not manifest. The procedures searching for the mutations that are dominant lethals in one genome but not dominant lethals in another genome have been designed. The new class of mutations was named conditional mutations and the genes responsible for their formation and carrying them, ontogenes [3, 4, 5]. The name “ontogenes” results from the property of these mutations to form monstrous structures (morphoses).

2. Generation of mutations in ontogenes and maintenance of mutations in culture

2.2 Generating mutations in drosophila

Drosophila is a convenient organism for the search for the above-defined mutations. The sons were obtained from the γ-irradiated drosophila females (Figure 1); part of these sons presumably carried the target mutation in the X chromosome. As was assumed, the homozygosity for the mutation in the X chromosome (males carry one X chromosome) should guarantee the viability of mutant males. All produced males were individually mated with females; the males that did not give daughters (heterozygotes for the mutation in the X chromosome) were regarded as mutant [8, 9]. The obtained mutations matched the defined requirement, namely, they were viable in males (homozygous for mutation) and lethal in females (heterozygous for mutation).

The main point in this technique is to detect the genes that are lethal in heterozygote (dominant lethals). The first batch of the mutants demonstrated that the dominant lethality of the obtained mutants was conditional. This lethality depends not only on the mutation itself but rather of on the genome accommodating this mutation and even on the genome of the mating partner. The mutations were named conditional [10] and two additional methods for their generation were proposed. In the first variant, the condition for non-manifestation of a lethal in the chromosome was an inversion in the opposite chromosome [11] and in the second, the condition for non-manifestation of a lethal in the X chromosome was a normal genetic constitution of the mating partner [12]. Once the development of monstrosities was recorded in the mutants, we started to detect the mutants in F₁ according to these monstrosities [13]. Further, having found out that the conditional mutations under permissive genetic conditions are always represented by recessive lethals;, we started to select the target mutation from the our collections of recessive lethals [12]. The collection of the drosophila conditional mutations maintained in laboratory at certain times reached a hundred and more variants in the X, 2, and 3 chromosomes.

2.3 Maintenance of conditional mutations in culture

Conditional mutations were maintained in cultures, depending on specificity of each conditional mutation. Conditional dominant lethals in the X chromosome were maintained in two ways (Figure 2). With the first way (Figure 2A), the culture contained females, heterozygous for the mutation and the Muller-5 inversion. Females produced In (1)M-5 sons and “+” sons with the mutation. The latter were fertile, but no +/+ females appeared in the culture because the effect of the mutation was lethal in the homozygous females. With the second way (Figure 2B), the mutant X chromosome was transmitted paternally only so that females in the line contained attached-X chromosomes. Conditional recessive mutations in the X, derived from typical recessive lethals by the Muller-5 method, were maintained as typical recessive lethals in the X chromosome. Conditional dominant lethals in chromosome 2 were maintained in culture containing the In(2LR)Curly inversion. Homozygotes for every one chromosomes 2 were lethal. Conditional dominant lethals in chromosome 3 were maintained in culture containing the In(3LR)Dichaete inversion. Homozygotes for every one chromosomes 3 were lethal.

3. Manifestation of mutations in ontogenes

The manifestation of mutations emerged to be numerous and diverse. Some of them are completely unexpected and fantastic, such as the development of monstrosities or changes in the basic metabolism, and others are observable although rarely in common Mendelian mutations (parental inheritance and genetic instability); however, some manifestations are well known for common mutations. The conditional mutations are described in detail in reviews [14, 15]. Here, we give only a brief description to outline these manifestations.

Most of the conditional mutations are dominant lethals. These mutations are characterized by the permissive genetic conditions (genotype) under which a dominant lethal can exist in the organism without leading to its death and the restrictive conditions (genotype) under which its manifests itself. An example is the offspring of the drosophila males carrying a dominant conditional mutation in the X chromosome (Table 1). The mutation has no lethal effect in the organism of males but kills the daughters that would form in the crosses of these males with yellow females.

In this case, the factor that saves the males from death is their gender (male). In the case of some of the generated dominant conditional mutations, the dominant lethality is eliminated by a chromosome rearrangement in the opposite homolog [11], in a nonhomologous chromosome [12], or even in the genome of the mating partner [12]. The permissive conditions remove the dominant lethality of mutation; however, recessive lethality remains so that the homozygotes for mutation die. Recessive lethality under permissive conditions is an obligatory attribute of conditional mutations.

The fact of a recessive lethal manifestation makes it possible to test the mutations for allelism. No alleles have been detected in the large collections of the mutations in the X chromosome (about 60 mutations) and autosome 2 (about 20). The death of mutants in a homozygous state and their survival in a heterozygote with other mutations means that conditional mutations are discrete regions of DNA molecules. Ten conditional mutations in chromosome 2 that displayed recessive lethality were mapped with the help of a standard set of deletions. Half mutants contained two and more lethal defects. These data suggest that the regions of multiple recessive lethality lethalities emerge in a secondary manner under the effect of the earlier formed radiation-induced mutation in ontogene [17].

The conditional mutations with a visible manifestation constitute a separate group. The Smba (Small barrel) mutation has a dominant phenotype appearing as a shortened body and short pupae. The presence of the In(2LR)Pm inversion in the opposite chromosome 2 removed this manifestation. The group of conditional mutations with the phenotypes scute, radius incompletus, and white apricot manifests only in females, while the corresponding males have a normal phenotype. These mutations were named dimorphic [14].

The permissive genetic conditions allow the dominant lethal mutations in heterozygote to avoid lethality. However, this does not mean that the heterozygotes become completely normal. They have an abnormally high level of locomotor activity and basic metabolism. In addition, they display genetic the instability appearing as (1) activation of the mobile element Dm 412; (2) formation of visible secondary mutations; (3) development of modifications and monstrosities (morphoses); (4) loss of dominant lethal manifestation of mutation with preservation of recessive lethality; and (5) loss of the manifestation of the visible dominant mutations in the chromosome opposite to the mutant homolog [14, 15, 18, 19].

Figures 3 and 4 show examples of modifications and morphoses in the offsprings of mutants. The share of the individuals with morphoses in the offspring of a mutant fly can reach several tens of percent [20, 21]. Because of a strong effect on ontogenesis, the genes responsible for generation of conditional mutations were named ontogenes [3, 4, 5]. For the sake of brevity, the mutations in ontogenes are hereinafter referred to as ontomutations.

A specific feature of ontomutations is that their manifestations are inherited in a parental manner. Thus, the morphoses in a heterozygote for an ontomutation emerge not only in the offsprings that received the ontomutation but also in the offsprings that have not received it [22, 23]. An example of the parental effect is evident for the ontomutations that cause the death of daughters in the crosses with yellow females (Table 1). The share of dying eggs in the cross is very high (over 50%); this suggests the death not only of the daughters that received the ontomutation, but also of part of the sons that have not received the ontomutation. Meiotic abnormalities hold a special place among all manifestations of ontomutations. This consists in of a high level of chromosome nondisjunction and loss [24] and will be separately considered below.

The pattern of ontomutations manifestations suggests that ontomutations are formed in the genes dissimilar to Mendelian ones. The absence of the own morphological “face” of the majority of ontomutations, the dependence of manifestation on different genetic factors, and the development of morphoses demonstrate that the main function of ontogenes is the regulatory function. However, it has emerged rather difficult in the characterization of ontogenes to advance further than the mere statement of “dissimilarity” and “regulatory character”. The range of biological phenomena to be considered and understood appeared to be considerably wider as compared with the Mendelian mutations.

Eventually, it appeared possible to approach the resolution of the question on the nature of ontogenes, namely, on what is their biological mission, in which tissues and at which time moments they are active, and what are the forms of this activity. Find below the step-by-step theoretical analysis of the phenomenology of conditional mutations.

4. Manifestation of ontogenes and distant hybridization

Some signs resembling the abnormalities characteristic of distant hybridization were evident in the manifestation of ontomutations. It was reasonable to perform a detailed comparison since a similarity would allow ontogenes to be regarded as the genes responsible for species specificity (membership).

Distant hybridization is the cross of the individual belonging to different taxa (species, genera, families, etc.) [25]. This hybridization is accompanied by the pattern of abnormalities that is independent of a particular cross and of the kingdom to which the parents belong (animals or plants).

The pattern of abnormalities (that is, the pattern of interspecific incompatibility) comprises (1) a high sterility of the cross; (2) parental effect when producing the hybrid; (3) phenotypic mosaicism of the hybrid; and (4) meiotic abnormalities of the hybrid leading to sterility [25, 26]. Characteristic of the ontomutations that we have generated are

1. Sterility of the cross. Ontomutations are conditional dominant lethals. The offspring in the crosses of ontomutants can be absent in part or at all. As an example, Table 2 shows the results of crosses between the strains carrying ontomutations in chromosome 3 [14].

   The males of strain 46 in the crosses with females 34 or 55 give no offspring at all but give offspring with the females of strain 27. The cross of strains 55 and 34 gives no normal offspring but the crosses of mutants of strains 55 and 34 with other strains give normal offspring.

2. Parental type of inheritance:. This type of inheritance is a character of the manifestation of ontomutations. Table 2 clearly demonstrates this effect: two pairs of ontomutations (34 and 46) and (46 and 55) give offspring in one cross direction but do not give it in the opposite direction. Ontomutations display most different forms of the parental effect, both rare in Mendelian mutations or absent at all. This comprises paternal inheritance and paternal–maternal variant [22, 23]. All forms of paternal effects in ontogenes have been described in detail [22, 23, 27].

3. Mosaicism. Mosaic fragments are frequently observed in the ontomutants [20, 21]. See Figure 5 for examples of mosaic phenotypes in ontomutants.

4. Meiotic abnormalities:. An extremely high frequency of the X chromosome nondisjunction in meiosis is observed for 30 ontomutations in the drosophila X chromosome [7, 24]. Table 3 lists the regular and exclusive offsprings of a drosophila female carrying an ontomutation in the X chromosome. The rate of matroclinous daughters (for the X chromosome) reaches 24.7%. In addition to nondisjunction, a loss of the X chromosome is observed and part of the nondisjoined X chromosomes had undergone exchange. A high rate of the X chromosome nondisjunction in drosophila females has a trend of inheritance for the daughters. These data suggest a deep interference into the meiotic division in the ontomutants [24].

As is evident, the pattern of aberrations in the ontomutants is similar to that of the interspecific incompatibility. The question is what the cause of incompatibility is. The heterozygosity in Mendelian genes cannot be the cause of incompatibility because heterozygosity does not lead to lethality in an intraspecific hybridization; moreover, it frequently leads to heterosis. In addition, the mutations in Mendelian genes do not interfere with meiosis and the corresponding mutants are viable even in compounds with deletion. It is clear that the heterozygosity in Mendelian genes cannot be responsible for interspecific incompatibility. Correspondingly, the cause underlying the incompatibility is the heterozygosity in the genes that determine the species membership. In their native genome, these genes are in a homozygous state and thus properly fulfill their role.

The similarity between the manifestations of ontomutations and the pattern of interspecific incompatibility in distant hybridization suggests that (1) the ontogenes belong to the group of the genes responsible for intraspecific similarity and (2) an unusual phenomenology of ontomutations results from their heterozygosity for ontogenes. The latter is similar to the heterozygosity in distant hybridization but is reached in another way. We generate ontomutations with the help of mutagenesis and get heterozygotes for an ontogene by combining them with an initially normal ontogene. Indeed, it is necessary to take into account that all genes responsible for the species membership in an interspecific hybrid are in a heterozygous state versus only one gene (ontogene) in the experiments with ontomutations.

The observed similarity to the pattern of interspecific incompatibility considerably simplifies the understanding of the role of ontogenes in the organism. Any “incompatibility” does not exist for the Mendelian genes and the phenomenon of interspecific incompatibility is determined by the conflict of the genes that form the species specificity of organisms rather than the Mendelian genes. The ontogenes belong to the former group of genes. It is useful to recreate in mind the pattern of incompatibility in distant hybridization to enhance the understanding of the role of ontogenes. Incompatibility is the result of heterozygosity for ontogenes.

5. Ontogenes and construction of cell ensembles

The biological mission of ontogenes was clarified when studying the phenomenon of development of monstrosities (morphoses) in the offspring of an ontomutant (Figures 6 and 7). In genetic literature, morphosis is defined as a nonadaptive and typically unstable variation of individual morphogenesis associated with a change in the external environment [28, 29, 30, 31]. Here, the term morphosis is used to designate the nonheritable morphological abnormalities caused by specific genetic features of the parent itself rather than by the external conditions; correspondingly, they may be referred to as “endomorphoses” unlike the earlier known “exomorphoses” [21].

The morphoses emerging in conditional mutants are the abnormalities of different degrees of manifestation. Most of them do not prevent flies to hatch from pupae, live, mate, and even give giving offspring. An experimenter working with drosophila for a sufficiently long time has undoubtedly encountered the cases of morphosis development but such cases are very rare. However, morphoses frequently emerge in the offspring of the generated conditional mutants [20, 21]. Soon after commencement of the work with conditional mutations, the collection of colored images of morphoses became very large (about 1000). The diversity and morphological complexity of morphoses are great [32]. The morphological defects are also characteristic of Mendelian mutations but the latter are is incomparably simpler.

The asymmetry of morphoses is the decisive phenomenon in the understanding of the role of ontogenes. Unlike a bilaterally symmetric morphological defects caused by Mendelian mutations, morphoses are asymmetric: as a rule, they are present on one side of the body (left or right) [33]. The bilateral asymmetry can be certainly regarded as a cell-level phenomenon. The asymmetry results from an incorrect spatial arrangement of the cells formed by division. Thus, it turns out that ontogenes do control the growth of embryo, its size, and spatial symmetry; moreover, the defects in ontogenes (ontomutations) make asymmetric the normally symmetric structures. The Mendelian genes control production of proteins in cells but do not control the arrangement of cells. That is the reason why Mendelian genes do not interfere with a bilateral symmetry [33].

The involvement of ontogenes in cell spatial arrangement is confirmed by the meiotic abnormalities in ontomutants. As is shown in Section 3, the ontomutations in a heterozygote significantly interfere with the normal meiosis. As is known, the heterozygotes for Mendelian mutations have normal meiosis [34]. Correspondingly, it is reasonable to assert that ontogenes control cell division (in this case, meiotic division) and Mendelian genes do not. Summing up, the phenomenon of asymmetry of morphoses together with the phenomenon of disturbed meiosis in ontomutants suggests that ontogenes are actually responsible for the construction of cell ensembles.

It is valid to regard that the “key players” in ontogenesis are now found: they are the ontogenes and Mendelian genes. The former (ontogenes) control the construction of cell ensembles, while the latter controls the production of protein sets in the cells forming the ensembles. To make the picture complete, it is logical to assume that ontogenes also switch on the Mendelian protein-coding genes. The patterns of morphoses in the individuals carrying ontomutations together with mutations in Mendelian genes confirm this assumption.

Consider an example when an additional small head has developed in a fly at the place of the right eye because of a mutation in ontogene (Figure 8). Since ontogenes switch on Mendelian genes, the mutant for the Mendelian mutation Bar displays the Bar phenotype not only for the normal left eye, but also for the aberrant right eye on the newly formed additional small head. It is evident from the available large collection of morphosis images that although the monstrosities are manifold and unusually located, the traits in morphoses that are definitely controlled by Mendelian genes (color of cuticle, eye color, and bristle color) are “switched on” correctly and perfectly fit the fly’s genotype. This “adjustment” of the Mendelian genes to the morphological structures despite their pathologies suggests that the event of the switch-on of the structures is automatically the event of the switch-on of a certain set of Mendelian genes.

The discussion of the mechanisms underlying ontogenesis after the works by Jacob and Monod [35] necessarily includes the idea of the regulator genes that trigger the structural genes. It is believed that the regulator genes belong to the category of protein-coding genes. Our data do not contradict the existence of protein regulators but suggest ontogenes as the key players in the organization of ontogenesis. Ontogenesis is not only the production of proteins, but also the production of the array of cells housing the production of proteins and ontogenes there are involved in the production of the cell array.

6. Activity of ontogenes in different tissues and at different developmental stages

The Mendelian genes are active in the soma from the very beginning of somatogenesis and to the end of life. According to the experiment, ontogenes are also active in: (1) the germline before meiosis (in premeiosis), (2) during meiotic divisions, and (3) in the zygote at the stage of synkaryon formation.

Premeiosis in germinal tissue:. A half of the offspring of a parent heterozygous for an ontomutation receives the mutation and the other half does not. However, the overwhelming majority of manifestations of ontomutations are observed in the entire offspring. This is true for the emergence of morphoses [22, 23], lethal effect of ontomutations [27], the effect of a chromosome rearrangement on the lethal effect of ontomutation [12, 36], the effect of the Y chromosome on the lethal effect of ontomutation [16], the effect of ontomutation on nondisjunction [24], and so on. All these cases of parental (maternal or paternal) inheritance mean that the mutant ontogenes are active in germline cells. The activity consists in the formation of the “factors” (it is not important which particular factors) that lose a physical link with the ontomutation (DNA region) whereby they originated. As a consequence, these factors after the reduction division equiprobably find themselves in both the gametes carrying ontomutation and the gamete lacking it.

Meiotic division:. Various meiotic abnormalities caused by ontomutations suggest that ontogenes are active in meiosis (see Section 3 and [24] for comprehensive description).

Synkaryon formation. The activity of ontogenes at this stage can be referred to as “the recognition of mating partner” [36]. The yellow females do not give daughters in the crosses with the males carrying an ontomutation in the X chromosome (Table 4). The prohibition for the presence of daughters in the offspring is removed if the females carry the Cy, Pm, or D inversion in autosomes 2 and 3. It is important that not only the daughters carrying the Cy, Pm, or D autosomes start appearing in the offspring but also the daughters without them. We have assumed that some tags appear on the chromosomes of female and male sets during the development of both the female and male gametes of ontomutants as early as the premeiosis. When the chromosome sets enter the zygote, the tags are compared and ontogenesis is triggered in the case the sets display similarity and does not in the absence of similarity [22, 23]. The zygote of drosophila dies at the stage of egg [22, 23]. Formally, this pattern is similar to that when the meeting of pronuclei is prevented, which is observed in genetic incompatibility in plants and protozoans [37, 38].

Ontogenesis of the soma. The development of morphoses suggests that ontogenes are active at this stage of individual development (see Section 5). A parental type of inheritance of these aberrations [22, 23] indicates that the genetic events in gonial cells are involved in their induction.

As is evident from the list of activities, ontogenes outdo the Mendelian genes in temporal and spatial parameters of their activity. The activity of ontogenes in germinal tissue, where Mendelian genes are inactive, is quite a surprise. The activity of ontogenes at different stages allows for the explanation of an intricate pattern of the ontomutation manifestations. For example, the combination of conditional dominant lethality with definite recessive lethality, illogical at a first glance, is explainable with that the former manifests itself during synkaryon formation and the latter, in the premeiosis of germinal tissue. The activity of ontogenes in the germline for the first time explains the radiation effects appearing as sterility and emergence of mutations in F₁ [39]. The observed activity of ontogenes in the germinal tissue puts the question on the forms of activity of ontogene DNA: a typical form of gene activity is coding for protein synthesis; however, no protein synthesis has been recorded in the germinal tissue.

7. Forms of activity of ontogenes

Activity as nRNA formation.: The chromosome rearrangements of inversion and translocation types interact with ontomutations [12]. The rearrangements themselves act as ontomutations decreasing fertility according to the parental effect [12]. The parental effect suggests the gene activity in the premeiotic cells of the germline. Thus, we may state that a certain chromosome rearrangement in these cells is active and the change in the activity of ontogenes is the result of its presence. Any rearrangement changes the distance between individual ontogenes. If the ontogenes in these cells “communicate” via nRNA, the change in the distances between ontogenes will quite expectedly lead to a change in the function. The lengths of the ways an nRNA have has to cover from an ontogene to another ontogene in a normal genome and in the genome carrying a rearrangement are different. Thus, nRNA can be a regulator of ontogene activity in the premeiotic germline cells.

Usually, proteins act as regulators of gene activity; however, a protein cannot act as a regulator of ontogene activity in germline cells in the case of a rearrangement. The schemes of regulation with the help of a protein and an nRNA are considered in a separate paper [5]. The way of a protein regulator have has to cover in this case (DNA–mRNA–ribosome–protein–DNA) is too long and passes through the cytoplasm. Such regulator will be unable to respond to the minor changes in the distances between ontogenes in the nucleus caused by a rearrangement. On the contrary, an immediate regulation of an ontogene by another ontogene with the help of an nRNA is feasible. All events (synthesis of nRNA and migration of nRNA) and all players (inducer ontogene and receptor ontogene) in this case reside within the nucleus ([5], Fig. 6). Thus, the most likely regulators of ontogenes are nuclear noncoding RNAs (ncRNAs). In this case, ontogenes act as both ncRNA inducers and ncRNA recipients.

The recent studies on genome-wide annotation utilizing high-throughput transcriptomics from a single- cell embryo to differentiated tissue cell types demonstrate that over two-thirds of the transcribed mammalian genome codes for tens of thousands of different classes of small and long noncoding RNAs (lncRNAs). The lncRNAs form the largest class of ncRNA subtypes. According to some recent estimates, there exist over 58,084 transcripts in the mammalian genome, which is larger than the number of protein-coding RNAs. In addition, lncRNAs appear to be key regulators in a wide range of biological processes, including cell proliferation, cell cycle, metabolism, apoptosis, differentiation, and pluripotency [40, 41].

It has become clear over the period from generation of the first batch of conditional mutations in Drosophila melanogaster in 2000 [8, 9] and a shorter time interval when lncRNA genes were studied [42, 43] that their biological functions are analogous. Both (1) are not protein-coding genes but control the operation of the latter; (2) are elements of the conserved part of the genome; (3) control the progression of ontogenesis and (4) phylogenesis; (5) are responsible for energy exchange in the organism; (6) control cell division; and (7) are inherited according to a parental type. Thus, these two groups most likely represent the same category of genes.

Conformation (coiling and remodeling) of DNA of ontogenes. The fact of a drastic disturbance of cell meiotic division in the presence of an ontomutation has been demonstrated (Section 3). If so, the ontogenes in meiosis are active even taking into account that the chromosomes in a meiotic cell are highly compacted. Thus, the activity is guided by highly compacted DNA of an ontogene and the parental effect on nondisjunction [24] suggests that this coiling “originated” from the premeiotic germline cells.

The previous section discusses the interaction between ontogenes in the zygote, when the parental chromosome sets meet after fertilization [36]. The parental chromosome sets are also highly compacted. The situation there is the same: the ontogenes are active although they are highly compacted. These two facts suggest that ontogene is a DNA sequence in a state of regulated coiling. A valid argument favoring this assumption has been earlier obtained by theoretical analysis of the pairing in a heterozygote for inversion [44].

The resulting conclusion focuses the attention on the studies that demonstrate the activity of heterochromatin blocks. Keeping in mind to do this large work in the future, see some studies indicating an important role of heterochromatin in the chromosome behavior in meiosis [45, 46, 47, 48, 49]. It cannot be excluded that the multilocality of some ontogenes that we have discovered by deletion mapping of ontomutations in chromosome 2 [17] is explainable with that the ontogenes are represented by coiled repeats. The pattern of somatic pairing in the regions of lncRNAs Firre in different chromosomes suggests the same inference [50].

Biophysical aspect of ontogene activity. The activity of ontogenes coming from compacted chromosome regions suggests that the mutual spatial arrangement of the DNA regions belonging to ontogenes is functionally significant. The studies into the effect of lncRNAs on DNA remodeling [51, 52, 53] confirms this. Having commenced the work with mutations in ontogenes, we encountered the cases of interaction of the ontogenes separated by considerable distances [44, 54, 55]. The simplest case is the interaction of the ontogenes that leads to the pairing of homologs in meiosis [44]. Note that the DNA of ontogenes in this process is in a coiled state. It is logical to assume that the forces emerging as a result of coiling of lncRNA regions are the factor that brings the homologs together, however, the mechanism of action of this factor is not clear. The new genes, which undoubtedly exist, fulfill the functions that cannot be implemented by Mendelian genes. Unlike the Mendelian genes, responsible for de novo protein synthesis, ontogenes control the template-based reproduction of DNA molecules as well as the reproduction of the cell itself via its division. In that case, the new genes must possess the capabilities that the Mendelian genes lack. Otherwise, the Mendelian genes themselves could cope with this task.

8. Ontogenes and problems in genetics

Currently, the ontogene, similar to the gene in the early days of genetics, is still hypothetical. The particular solutions will appear in the experiments; however, theoretical studies are also necessary. The specific feature of the moment is in that the concept of ontogene is introduced after a long period when the concept of gene represented by a protein-coding gene variant is a sole (universal) hereditary unit. The possible existence of other kinds of genes besides the Mendelian genes have been asserted by de Vries [56], Filipchenko [57], Timiryazev [2], Timofeev-Ressovsky in his first interpretation of the mutations with a varying manifestation [58], and in the hypothesis by Altukhov and Rychkov on the role of special (unchangeable) genes in speciation [59]. These hypotheses have not been further developed because of “objectlessness”: the experimental genetics of that time did not know any other genes except for the Mendelian genes. The discovery of mutations in ontogenes, no matter how “strange” they may be, changes the situation. Theoretical discussion of the genetic problems where the concept of ontogene (or its molecular analog, lncRNA gene) can be utilized seems most important

If we admit the existence of ontogenes, the structure of biological characters becomes universal and simple. Each character comprises (1) the cellular basis and (2) the proteins filling the cells. A Mendelian (simple or monogenic) character is regarded as a virtual structure in which its cellular basis is meant to exist but does not considered, while the protein contained in it is considered. On the contrary, cellular basis of the species-, genus-, family-level, etc. characters is considered but their protein content is omitted.

9. Conclusions

Mutagenesis acts as an architect of the living. Theoretically, only mutations give the possibility to (1) expand the potential of an existing biological species and (2) create new species. Mutations in Mendelian genes actually manage to fulfill the first task but fail in the latter [10, 60]. As has emerged, the problem has a simple solution: in addition to Mendelian genes, the genome contains the genes belonging to another category. Earlier, the mutations putatively belonging to this new category have been generated for drosophila. The new mutations were named conditional and the new genes, ontogenes. Currently, it is most possible that lncRNA genes are the molecular analogs of ontogenes. Here, we attempt to construct the phenomenology of conditional mutations, described earlier, into a logically arranged pattern representing a special part of the genome composed of ontogenes. The work of Mendelian genes on the production of proteins is unfeasible without the ontogenes. The arguments favoring a common nature of ontogenes and lncRNAs are considered in the paper.

The category of genes responsible for the specific outlook of a species is not visible in the case of an intraspecific hybridization but becomes evident in distant hybridization as the syndrome of interspecific incompatibility. The pattern of ontogene manifestation repeats the pattern of interspecific incompatibility. This means that the ontogenes belong to the category of genes that determine the species' specificity. The patterns of monstrosities and meiotic abnormalities reveal the main mission of the ontogenes, namely, the control over construction of cell ensembles in ontogenesis. Concurrently, they also include the Mendelian genes that control protein synthesis.

The ontogenes are active in every living cell in a spatial aspect in the germline and soma and in a temporal aspect, starting from the gonial divisions to the renewal of differentiated somatic cells. Our data suggest us that an event of genome editing, taking place in the premeiosis and involving ontogenes, precedes the formation of every gamete. The specific features in the function of ontogenes underlie the following characteristics untypical of the Mendelian genes: (1) dominant lethal effect; (2) conditional effect; (3) parental inheritance; (4) decrease in fertility; and (5) integral forms of variation referred to as individual and epigenetic variations.

Acknowledgments

The authors thank the Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences, for financial support of this work (budget project no. 0259- 2021-0011).