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Allelic variants of hereditary prions: The bimodularity principle

ABSTRACT Modern biology requires modern genetic concepts equally valid for all discovered mechanisms of inheritance, either “canonical” (mediated by DNA sequences) or epigenetic. Applying basic genetic terms such as “gene” and “allele” to protein hereditary factors is one of the necessary steps toward these concepts. The basic idea that different variants of the same prion protein can be considered as alleles has been previously proposed by Chernoff and Tuite. In this paper, the notion of prion allele is further developed. We propose the idea that any prion allele is a bimodular hereditary system that depends on a certain DNA sequence (DNA determinant) and a certain epigenetic mark (epigenetic determinant). Alteration of any of these 2 determinants may lead to establishment of a new prion allele. The bimodularity principle is valid not only for hereditary prions; it seems to be universal for any epigenetic hereditary factor.


INTRODUCTION
All fundamental genetic terms (gene, allele, genotype, mutation, recombination, etc.) were introduced just to describe genetic phenomenology and initially lacked any relation to certain types of biomolecules. After the genetic role of DNA had been demonstrated, 1,2 it has been strongly believed that all hereditary factors were represented by DNA, and that DNA sequencing was enough to unravel the origin of any hereditary differences in any species. As a result, all genetic terms became associated with specific processes affecting DNA sequences. Discovery of epigenetic, especially protein, inheritance opened a new era in biology and raised a lot of problems in genetic concepts. The fundamental genetic terms became fuzzy and thus called for reconsideration (for a review see refs. [3][4][5]. Modern biology requires modern genetic concepts valid for all discovered mechanisms of inheritance, either "canonical" (mediated by DNA sequences) or epigenetic. One of the most intriguing epigenetic phenomena is protein inheritance, the field of genetics where hereditary factors are represented by proteins.
Currently, the scope of phenomena related to protein inheritance includes positive feedback by means of transcription factors, [6][7][8][9] cortical inheritance, 10 centriole inheritance, 11 and hereditary prions. 12,13 The latter are of special interest, because different variants (strains) of some hereditary prions have been disclosed (for a review see refs. [14][15][16][17]. Each of these variants is a discrete hereditary factor and should be described in basic terms of general genetics; so, it is not surprising that prions are sometimes viewed as "protein genes." [18][19][20] Moreover, prionization, as well as prion curing, are considered as "protein mutations," and different variants (native and amyloid) of the same prion protein are called alleles. 21 In a recent issue of Seminars in Cell and Developmental Biology, different variants (native and amyloid) of the same prion protein were called alleles, and conversion of the [prion ¡ ] state to the [PRION C ] state was designated as "protein paramutation." 22 The term "paramutation" is used when one allele is epigenetically converted after its presence in a heterozygote with another allele. Thus, the process of applying basic genetic terms for protein hereditary factors has begun, and it is one of the key conditions necessary for the establishment of modern genetic concepts. Along the same lines of reasoning, we will consider different variants of the same hereditary prion as prion alleles. Current data concerning hereditary prion alleles are very complex and strongly need generalization. The aim of this paper is not to scrutinize the details, but to review the basic principles underlying hereditary prion alleles.

Molecular Basics of Hereditary Prions
The term "prion" was introduced to designate a small proteinaceous infectious particle produced by the PrP protein in mammals. 23,24 Prion infectivity is based on prion self-perpetuation via changing the native protein isoform into the prion one, and newly appearing prion particles can be transmitted from one organism to another. 25 Taking into account the fact that in animals prions form only in somatic tissues, which do not transfer their properties to the descendants originating from the generative cells, prions had been considered as infectious agents only until 1994. Later, discovery of prions in some fungi substantially changed the initial paradigm: fungal prions are usually heritable as well. 26 In this review we will focus exactly on hereditary prions.
Currently, at least 4 molecular mechanisms underlying hereditary prion phenomenon are known: switch from native to amyloid conformation, positive feedback through protein phosphorylation by the MAPK-cascade, reproducible alterations in quaternary protein structure, and positive feedback through alterations in primary protein structure ( Table 1). The first one has been extensively reviewed elsewhere (for a review see refs. 13,[27][28][29], and therefore will be mentioned here just briefly.

Switch from Native to Amyloid Conformation
The term "amyloids" means non-covalent protein aggregates that (i) form unbranched fibrils, (ii) possess cross-b-structures, and (iii) have a core region extremely resistant to hydrogen/deuterium exchange, proteases, and chemical denaturation. 30 All the above mentioned amyloid properties have been proven for several hereditary prions, at least in vitro  57 Positive feedback through alteration in protein primary structure Constant activity of protease B S. cerevisiae 59 6 O. N. Tikhodeyev et al.
( Table 1), [31][32][33][34][35][36][37][38] while for some other prions these properties have been presumed rather than proven (for a review see ref. 13). Amyloid prion aggregates are self-perpetuating because they induce conformational switch of a certain protein from its native to amyloid isoform, thus templating their own reproduction. Different amyloid templates can be produced on the base of the same native isoform (for a review see ref. 13). This phenomenon is in good agreement with the fact that the same amyloid prion exists in multiple alleles differing from each other in their manifestation. [14][15][16][17] Heredity of amyloid prions is based on 3 processes (Fig. 1). The first is prion reproduction: a monomeric native protein interacts with a preexisting aggregate, changes its own conformation and incorporates into the amyloid fibril. As a result, the fibril elongates. The second process is prion multiplication: 39 the growing fibril is cleaved into fragments, producing aggregate seeds called propagons. 40 In most cases, cellular chaperone machinery performs this function; for instance, in the Saccharomyces yeast, the major role belongs to Hsp104 (for a review see ref. 13). The third process is prion inheritance. It is based on prion seed transmission from a cell to its progeny during cell division, mating, or hyphae conjugation.
Infectivity of fungal amyloid prions is typically provided by propagon transmission through cytoduction or local anastomoses. Moreover, it can be modeled using protein transformation with in vitro obtained prion aggregates or cellular lysates from a [PRION C ] strain. [41][42][43] Recently, it has been also proposed that propagons can be transmitted from cell to cell by extracellular vesicles. 44 The most extensively studied amyloid hereditary prion is [PSI C ], an aggregated form of Sup35p in Saccharomyces cerevisiae. 14 In its native conformation, this protein is soluble and functions as a component of the translational termination machinery. 45,46 Under some rare events with frequency about 10 ¡7 per cell, 47 it switches to atypically stable conformation, and the altered molecules are incorporated in the amyloid (for a review see ref. 39). When such aggregate interacts with the native Sup35 molecules, it converts them to the prion isoform too, and thus reproduces. Multiplication of this prion depends on Hsp104, which cleaves aggregates. 39 [PSI C ] is effectively transmissible through cytoduction, and is stably heritable both mitotically and meiotically. It decreases the efficiency of translation termination and behaves as a non-Mendelian nonsense suppressor. 48 Multiple [PSI C ] alleles distinct in their suppressor efficiency, mitotic and meiotic stability, the proportion of aggregated Sup35p, the number of aggregates per cell, and some other features are described (for a review see refs. 14,15,17,40,49,50). Formation, heritability and elimination of [PSI C ] depend on various genetic and environmental factors thoroughly discussed in prion literature (for a review see refs. 13,[27][28][29]. About a dozen of other amyloid hereditary prions are known in yeasts and Podospora anserina. The amyloid domains in these prions are non-homologous, and even distinct in their physical characteristics: some of them are N/Q rich, but others are not (for a review see refs. 12,13,18), so, the details of amyloid prionization seem to be specific in each case. Amyloid prions have been also described in mammals (for a review see ref. 51), but here they are only infectious, not heritable.

Positive Feedback Through Protein Phosphorylation by the MAPK-Cascade
This mechanism has been described in the filamentous fungus Podospora anserina. 52,53 The MAPK-cascade is a regulatory phosphorylation system typical for all eukaryotes and comprising 3 sequentially functioning protein kinases: MAPKKK, MAPKK and MAPK, where MAPK is phosphorylated by MAPKK which in turn is a target for MAPKKK (for a review see ref. 54). P. anserina possesses 3 autonomous MAPK pathways: PaMpk1, PaMpk2 and PaMpk3. 55 Activation of the PaMpk1 pathway results in crippled growth, i. e. in formation of poorly growing female-sterile pigmented flat mycelium. This phenotype is infectious, and its molecular basic is designated as the C prion. 52 PaMpk1 is normally activated during stationary phase and ceases after return to growth; such activation is infectious through local anastomoses for normal recipient strains, but is not heritable within the initial mycelium. However, when this pathway is occasionally triggered during the growth phase, it undergoes self-activation (molecules in the ON state activate those in the OFF state) and appears to be both infectious and mitotically heritable ( Fig. 2A). 53 So, at least 2 different forms of C are currently known: one is both infectious and mitotically heritable, and the other is only infectious. 53 It is unclear which element of the PaMpk1 pathway directly corresponds to C. C manifestation requires all 3 genes of the pathway (PaASK1, PaMKK1, and PaMPK1) and can be induced in the normally growing mycelium when any of them is overexpressed. 53,55,56 So, it is possible that C is determined by the state of the PaMpk1 pathway as a whole, and not by the state of a certain protein kinase. 55 C inheritance in the growing mycelium requires not only the PaMpk1 pathway, but also increased translational accuracy and some genes encoding NADPH oxidases. 53,55 Moreover, C can be cured by various stresses, including heat, UV light, some antibiotics, and high concentrations of sucrose. 52 The exact mechanisms of these effects are still obscure, but the appearance and the dissipation of C are undoubtedly under complex genetic, developmental and environmental control. The difference between C produced during the growing and the stationary phases is of special interest: the first is both infectious and heritable, while the second is only infectious.
Up to date, C remains the only known example of heritable unit caused by post-translational protein modification. However, since protein-based inheritance has been discovered just recently, other examples are possible. Theoretically, they can be determined by various types of protein modification, not only phosphorylation.

Reproducible Alterations in Quaternary Protein Structure
The unique example of this mechanism known so far has been described in the Saccharomyces yeast. It involves the complex of 2 non-homologous proteins: Pma1, an essential highly abundant P-type ATPase, and Std1, a component of the Snf3/Rgt2 regulatory pathway. Normally, Pma1 is associated mostly with the Std1 paralog Mth1. When Pma1 preferable interaction occasionally shifts from Mth1 to Std1, an abnormal protein complex designated as prion [GAR C ] forms and reproduces (Fig. 2B). 57 Recently, it has been shown that [GAR C ] is also induced by the presence of unknown bacterial chemical factors. 58 In the [GAR C ] cells, glucose repression is modified: these cells can grow in glycerol in presence of non-metabolizable glucose analog, glucosamine. 57 This phenotype is transmissible via cytoduction, and is steadily inherited both mitotically and meiotically. [GAR C ] formation is enhanced under STD1 or PMA1 overexpression, while MTH1 overexpression leads to the opposite effect. After [GAR C ] is established, it can be reversibly cured by transient lack of Hsp70 proteins Ssa1 and Ssa2. Moreover, [GAR C ] is totally cured when both STD1 and the N-terminus of PMA1 are deleted, but it reproduces in case only one of them is absent. 57 Thus, the exact molecular mechanism of [GAR C ] manifestation is unknown to date.

Positive Feedback Through Alterations in Primary Protein Structure
In all above mechanisms, the differences between the native and prion states do not affect primary protein structure. [b C ], a selfactivating form of yeast protease B, is the unique example of the opposite situation. 59 Protease B (PrB) is derived from a large catalytically inactive zymogene encoded by the PRB1 gene and undergoes several steps of maturation. 60 At final steps, the zymogene is truncated by protease A (PrA) and then by PrB itself: the mature molecules truncate the immature ones, thus producing a positive feedback loop. 61 The effectiveness of this loop depends on several genetic and environmental factors. On YPAD medium, PrB self-activation is PrAdependent. 62 As a result, deletion of PEP4 (the gene coding for PrA) leads to gradual decrease and eventual loss of active PrB; however, this loss is delayed, and the residual PrB activity lasts at least for 20 mitotic divisions. This effect is called "phenotypic lag." 63 On YPG medium, PrB is autonomous and does not require PrA activity; so, the cells display steady PrB self-activation even when PEP4 is deleted. When such cells are transferred to YPAD, they eventually lose active PrB and fail to restore it after return to YPG (strictly speaking, the restoration is possible, but it requires PRB1 overexpression). Thus, when PRB1 is normally expressed, 2 kinds of cells having exactly the same DNA background and differing only in their PrB state can be obtained on YPG medium: PrB positive ([b C ]) and PrB negative ([b ¡ ]). 59 [b C ] is stably heritable in both mitotic and meiotic generations, and can be effectively transmitted by cytoduction. So far, it is the unique hereditary factor reproducing through protein primary structure changes.

The Bimodularity Principle of Hereditary Prion Alleles
According to conventional criteria, hereditary prions are (i) non-Mendelian elements, (ii) reversibly curable by anti-prion agents, (iii) depending on the corresponding gene, and (iv) capable to appear de novo when this gene is overexpressed. 26 The third point is of special importance for us. It means that allelic hereditary prions obligatorily depend on the same gene, and here is the way to uncover their allelism. For example, no [URE3] allele can be reproduced under the lack of the URE2 gene, and hereby any of them is quickly lost. 26 13). Therefore, to prove that certain hereditary prions are allelic to each other, both the third and the fourth criteria should be met. This approach is successful even for those prion alleles which significantly differ in their manifestation, like strong [PSI C ] and [ETA C ]. 49 It is obvious from the above criteria that to perpetuate a certain [PRION C ] allele, 2 kinds of molecular structures are required: (i) the protein structure (chemically modified, truncated or conformationally altered) as a seed, and (ii) the corresponding DNA sequence, otherwise the prion will not be reproduced due to the lack of the necessary protein. So, a [PRION C ] allele is a bimodular hereditary system that depends on the certain DNA sequence (DNA determinant) and the certain epigenetic mark (epigenetic determinant). The first encodes the prion protein sequence, while the second describes the state of this material, and both affect prion functions and evolution. 64 Notably, the presence of a certain [PRION C ] allele in a cell does not mean that all molecules of the corresponding protein are transformed into the prion state: some portion of the native protein is also retained. [65][66][67] So, the symbol [PRION C ] signifies the availability of specific epigenetic mark, which is absent in the [prion ¡ ] cells.
One can distinguish 3 types of differences between prion alleles. In the simplest case, these differences are solely of epigenetic origin, like between strong and weak [PSI C ] variants independently produced in the same SUP35 background. 14 Such prion alleles are encoded by the identical DNA determinant and vary just in epigenetic marks. On the contrary, some prion alleles are identical in their epigenetic mark, but differ in the DNA determinant. This is typical to cytoductants with various SUP35 backgrounds to which the same [PSI C ] template has been transmitted. 20,68 And finally, in most complicated cases, the differences between prion alleles affect both DNA and epigenetic determinants. The 2 distinct [PSI C ] prion variants are remarkable example: the strong one produced by the normal SUP35 molecules, and the weak one induced in the SUP35 PNM2 background (hereafter referred as strong [PSI C ] and [VH-1], respectively). 14,15 The fact that even such prion variants are allelic to each other can be proven by the following simple logic. [VH-1] is reproducible in the normal SUP35 background. 15  Thus, prion alleles are considerably more sophisticated hereditary factors compared with DNA alleles or epialleles. Prion alleles are bimodular: their diversity displays variation in both DNA and epigenetic determinants, and alteration in either of these determinants can result in the appearance of a new prion allele. So, we propose bimodular designation of each prion allele: "DNA determinant [epigenetic determinant]." It should be especially noted that the DNA determinant is not a part of prion allele; its presence in a certain bimodular designation just definitely describes the corresponding protein sequence.
Usually both determinants of a certain prion are represented by a set of multiple variants, and each combination corresponds to a potential prion allele. This diversity is restricted by cell lethality or prion loss in specific combinations (see below). Some prion alleles are distinct in their manifestation, while some are phenotypically indistinguishable from each other, like DNA sequences with synonymous polymorphism.

Implications of the Bimodularity Principle for the [PSI C ] Prion
As noted above, [PSI C ] exists in multiple alleles distinct in their mitotic and meiotic stability, nonsense-suppressor efficiency, the proportion of aggregated Sup35p, the number of propagons per cell, and some other properties. In addition, the absence of the prion particles is considered as a null-allele, [psi ¡ ]. The aim of the following sections is to overview the principal variety of prion alleles and potential types of their interactions on the example of the [PSI C ] prion. should interact with each other with respect to their reversibility to the [PSI C ] state. Depending on the combined null-alleles, the results of interaction may be diverse. We will focus just on several examples. In the simplest cases, clear dominance is expected. For instance, when one null-allele is reversible and another is irreversible (SUP35 DN [psi ¡ ]), the first should dominate over the second. However, this effect cannot be detected in common way through arising of colonies with [PSI C ]-mediated nonsense suppression, since N-truncated Sup35p is never included in the prion particles and thus provides adequate termination at nonsense codons. 69 Dominance may also take place when each null-allele is reversible alone, but one of them has PNM ("psi-no-more") manifestation.  3 types of the prion particles should be produced. Two of them correspond to the initial [PSI C ] alleles, and the third is mosaic; its amount depends on the efficiency of cross-templating. In tetrad analysis, the ascospores produced by such hybrids should contain a mixture of different [PSI C ] particles, but further, at the level of growing colonies, clear 2 : 2 ratio must be established, reflecting meiotic segregation of the DNA determinants. Here, the initial [PSI C ] alleles behave like classical Mendelian hereditary factors.
In most complicated cases, when the combined [PSI C ] alleles differ from each other in both DNA and epigenetic determinants, various types of interaction are theoretically possible (Fig. 3). They include (i) stable co-existence of the initial [PSI C ] alleles (Fig. 3A), (ii) appearance of mosaic particles and "recombinant" [PSI C ] alleles in addition to the initial ones (Fig. 3B), and (iii) competition between the initial and/or recombinant [PSI C ] alleles leading to eventual loss of the weakest one(s) (Fig. 3C). Depending on the type of these interactions in certain diploid, the results of tetrad analysis may differ.

Combination-Specific Interplays Between the DNA and Epigenetic Determinants in the [PSI C ] Cells
Three types of such interplays are currently described. First, some combinations are lethal; 49,77 15,70,74,75,80,81 Interestingly, the "reciprocal" combinations are quite stable: overproduction of SUP35 PNM2 induces the rise of specific SUP35 PNM2 [PSI C ] alleles, templates of which are efficiently reproduced by SUP35 ref . 15 In theory, combination-specific [PSI C ] loss may also occur due to positive selection of the  70,82 So, transmission of a certain [PSI C ] allele from one DNA determinant to another and back is sometimes not a "true reversion." In the third type of the interplays, each combination of the DNA and the epigenetic determinants, when isolated in a single cell, may behave as a separate prion allele. However, in the first and the second types, the corresponding combinations per se are not prion alleles because of their inability to perpetuate in the progeny due to either lethal effect or [PSI C ] to [psi ¡ ] conversion.

Non-Multiplied or Non-Reproduced States of [PSI C ] Alleles
Under the lack of Hsp104 chaperone function (for example, during GuHCl treatment or in strains with HSP104 deletion), the [PSI C ] particles are not multiplied, and fail to produce new prion seeds. 39,40,83,84 As a result, the nonmultiplied [PSI C ] particles (we propose to designate them by subscript, [PSI C ] M¡ ) are progressively diluted in cell divisions, and after approximately 15 cell cycles the overwhelming majority of the mitotic progeny is cured. 40,84,85 But the residual amyloid fibrils do not vanish: due to continuous Sup35p aggregation, they become extra long and usually remain in the mother cell because of asymmetric division in the Saccharomyces yeast. 86 However, the initial [PSI C ] allele appears to be intact, and may be multiplied and inherited after Hsp104 function is restored. 40,84,85 Thus, the [PSI C ] M-particles are hereditary factors, which retain their allelic specificity and can be potentially rescued for the progeny. We should also mention that [PSI C ] multiplication depends on the balance between various cellular chaperones, and any disturbance of this machinery may have remarkable consequences on the prion properties. [87][88][89][90][91][92] In theory, the [PSI C ] M¡ state may exist even under normal chaperone function. This state could be characteristic to SUP35 mutants in which the produced prion particles are not amenable for chaperone-mediated cleavage as a result of some defects in the Sup35p N-terminal region. However, such mutants are still unknown. And even if they do exist, the corresponding particles should be quickly cleared from the culture due to infinite enlargement and poor heritability.
Another atypical state of [PSI C ] alleles can be obtained when the prion particles are transmitted to a cell lacking both Hsp104 function and the DNA N-determinant. Under these conditions, when the [PSI C ] particles are neither reproduced nor multiplied ([PSI C ] R-M-), the overwhelming majority of the mitotic progeny should be SUP35 DN [psi ¡ ], while some cells can retain a single or few prion particles. The [PSI C ] R-M-amyloid fibrils do not enlarge and thus are potentially heritable. They can be rescued through cytoduction to a SUP35 ref recipient with normal Hsp104 function.
The non-reproduced state of a [PSI C ] allele resembles "canonical" DNA allele in a non-replicative plasmid: both will be The simplest situations are considered. To describe more complicated ones, the proposed designations should be combined appropriately.
Alteration of a [PSI C ] allele due to substitution of the DNA determinant is not a single-stage process. If the new DNA determinant is compatible with the initial conformational template, the prion fibrils become mosaic; they contain 2 Sup35p variants ("old" and "new"), and the portion of the former gradually grows up. This eventually results in complete loss of the "old" Sup35p variant, and from that moment the new [PSI C ] allele is established. Notably, the transitional stage between "old" and "new" prion alleles corresponds to classical pre-mutational DNA mismatch where the bases of both "old" and "new" alleles are simultaneously present. The main difference is that in case of prion alleles, the transitional stage is gradual and more prolonged. (c) For each type of heterozygotes, only one certain example is shown. If a heterozygote is produced by genetic cross, the first written prion allele is of MATa parent. If a heterozygote is produced by genetic transformation of a haploid strain, the first written prion allele is encoded by chromosomal DNA determinant.   reproduces under STD1 deletion, 57 the exact molecular basis of this prion is still questionable.

CONCLUSIONS
In this paper we have further developed the ideas of Chernoff and Tuite about prion alleles. 21,22 Prion allele is considered as a bimodular hereditary system which depends on a certain DNA sequence (DNA determinant) and a certain epigenetic mark (epigenetic determinant). The first encodes the prion protein sequence, while the second reflects the presence or absence of specific prion seeds. Bimodular designation of each prion allele (DNA determinant[epigenetic determinant]) is accordingly proposed.
It has been widely accepted that prions are "protein-only" hereditary factors. This is true in vitro, where native molecules of a certain prion protein are placed, and the only factor required for their prionization is addition of the corresponding prion seeds. But in vivo the situation differs markedly: when the DNA determinant is absent and native molecules are also lacking, there is no material for prionization even if the prion seeds are transferred to the cell. Thus, the "protein-only" concept is not universal and should be replaced by the bimodularity principle.
This principle is an appropriate generalization in prion studies, and its foresights can be found at least in several prion-related papers. For instance, amyloid prions are sometimes considered as conformational ("second order") templates in addition to DNA ("first order") ones. 4,101,102 This view is quite close to the bimodularity principle, but does not cover non-amyloid hereditary prions which reproduce via positive feedback loops without second order templates. The fact that prion function and evolution are affected at 2 levels (DNA and protein) has been recently pointed out by Wickner and Kelly. 64  where the initial DNA determinant is written within square brackets and the new one is not. The bimodularity principle is devoid of the aforementioned disadvantages. It gives useful and consistent designations of the DNA and epigenetic determinants, prion alleles, their alterations, non-multiplied and non-reproduced states, etc. (Table 2). Moreover, it is applicable to any hereditary prion allele, whenever it is amyloid or non-amyloid.
In accordance with the bimodularity principle, we distinguish 3 types of prion allele differences. They may affect the DNA determinant only, the epigenetic determinant only, or both. As a result, multiple [PRION C ] and [prion ¡ ] alleles can exist. Some of them are phenotypically distinct, while others are similar in their manifestation, like DNA sequences with synonymous polymorphism.
Although prion alleles are considerably more complex hereditary factors compared with DNA alleles and epialleles, there are a lot of remarkable similarities. Like "canonical" DNA alleles, prion alleles are multiple and highly polymorphic. They can transiently exist in the non-reproduced state similar to "canonical" DNA alleles expressed in a non-replicative plasmid. Alteration of a [PRION C ] allele due to substitution of the DNA determinant is not a single-stage process resembling pre-mutational DNA mismatch. Some prion alleles (for example, isogenic Like epialleles, isogenic [PRION C ] and [prion ¡ ] alleles differ from each other just epigenetically. Moreover, being combined in a heterozygote, they are involved in paramutation establishment. Thus, the term "prion allele" is appropriate for modern genetics. It should be especially noted that the bimodularity principle is applicable not only for hereditary prion alleles, but for any epigenetic hereditary factor (Table 3). So, this is an important step toward universal genetic concepts which should embrace all variety of hereditary factors irrespective of their molecular nature.

DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
No potential conflicts of interest were disclosed.