Epigenetic and eugenetic_processes

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ISSN 2079-0864, Biology Bulletin Reviews, 2016, Vol. 6, No. 4, pp. 333–343. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © O.N. Tikhodeyev, 2015, published in Uspekhi Sovremennoi Biologii, 2015, Vol. 135, No. 6, pp. 542–553.
Epigenetic and Eugenetic Processes
O. N. Tikhodeyev
St. Petersburg State University, nab. Universitetskaya 7/9, St. Petersburg, 199034 Russia
e-mail: tikhodeyev@mail.ru
Abstract—The term “epigenetics” is critically analyzed basing on the differential concept of variability. A
strict definition of epigenetic processes is proposed. The widely accepted tradition to oppose the words
“genetic” and “epigenetic” is shown to be incorrect. An adequate antonym for the term “epigenetics” is pro-
posed. Optimization of current genetic terminology due to epigenetics redefining is discussed.
Keywords: epigenetics, epigenetic inheritance, regulation of gene expression, prions, epigenotype, eugeno-
type, eugenetic processes, phenotype plasticity, differential concept of variability
DOI: 10.1134/S2079086416040071
INTRODUCTION
Modern biology cannot be imagined without epi-
genetics. Thousands of articles on various epigenetic
phenomena are published annually. However, so far in
scientific literature there is no generally accepted
notion what processes are to be called epigenetic
(Jablonska and Lamb, 2002; Haig, 2004; Korochkin,
2006; Chadov, 2006; Holliday, 2006). There are three
major points of view. Most often epigenetic processes
are considered as inheritance of regulatory states, i.e.,
such phenotypic changes that do not imply alteration
of the DNA primary structure (Riggs et al., 1996;
Richards, 2006; Vanyushin 2013). Meanwhile, in
opinion of many molecular biologists, epigenetic pro-
cesses include any local changes at the level of chro-
matin (Bird and Macleod, 2004; Berger et al., 2009).
Finally, the third interpretation relates to different
molecular mechanisms controlling gene expression
during ontogenesis (Nanney, 1958; Holliday, 1990;
Hall, 1992; Herring, 1993; Belousov, 2006).
It is important to note that this semantic ambiguity
reflects the general state of the genetic lexicon at the
edge of the 20th and 21st centuries. During the past
three decades, there have been huge discussions over
the question “What is a gene?” but no unequivocal
answer has been given (Beurton et al., 2000; Ratner,
2002; Chadov 2006; Gerstein et al., 2007; Falk, 2010).
Until recently, there was no clear boundary between
combinatorial and mutational variability, the term
“modification” remained very vague, and the term
“genotype” did not have a strict interpretation (Inge-
Vechtomov, 2010a, 2010b; Tikhodeyev, 2012, 2013).
This list can be continued with further examples.
Such problems arise due to the initially incorrect
integral concept of variability, which was established
in the early 20th century and is clearly outdated now
(Tikhodeyev, 2012, 2013, 2014).
INTEGRAL CONCEPT OF VARIABILITY
AS THE MAIN SOURCE OF GENETIC
TERMINOLOGY FUZZYNESS
In accordance with this concept, it was assumed
that three most important aspects of variability (fac-
tors generating variation of phenotypes, the molecular
nature of the arising differences, and ability of these
differences to be transmitted to progeny) closely cor-
relate with each other. As a result, it seemed self-evi-
dent that any genetic term must cover all these aspects
simultaneously.
The disadvantages of this concept are clearly visible
on the example of the terms “mutation” and “modifi-
cation” (environmental variation). The integral con-
cept of variability implied that not any acquired trait
can be inherited, and therefore the terms “mutation”
and “modification” were considered as antagonists
(Table 1). However, due to accumulation of empirical
data, numerous contradictions gradually arose. A
number of biological phenomena related both to
mutations and modifications have been described. In
particular, prolonged yeast cultivation in a medium
with guanidine hydrochloride results in complete
elimination of prion [PSI+] (Chernoff, 2001). This
change can be called mutation (it is persistently trans-
mitted from ancestors to progeny), but can also be
regarded as modification (it is induced by environ-
mental conditions, leads to predictable result, and
does not affect the structure of DNA). Another exam-
ple is elimination of some plasmids under prolonged
action of novobiocin in E. coli (Hooper et al., 1984).
This change is mutation (it is inherited and it affects
the DNA molecule), but at the same time refers to a
modification (it arises due to directional influence of
the environment). Finally, very unexpected combina-
tion of properties is typical to the D378N transition in
the expressed copy of yeast PMA1 gene. This transi-

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BIOLOGY BULLETIN REVIEWS Vol. 6 No. 4 2016
TIKHODEYEV
tion alters the primary structure of DNA without
being transmitted from ancestors to descendants (Har-
ris et al., 1994); therefore, it should be considered as
both mutation and modification. This resulted in deep
crisis that has no solution within the integral concept.
We have formulated the differential concept of
variability that makes it possible to overcome all above
contradictions. This concept comes from the fact that
different aspects of variability are autonomous from
each other and each of them requires specific termi-
nology (Tikhodeyev, 2012, 2013, 2015). Accordingly,
the terms “mutation” and “modification” are not
antagonistic anymore. The first reflects heritability of
changes regardless of their origin and molecular
nature, and the second refers to the result of direc-
tional environmental influences irrespective of its her-
itability and mechanism (Tikhodeyev, 2013, 2015).
Therefore, it is not surprising that they overlap in some
cases.
The differential concept of variability has already
given several important achievements: the problem of
numerous genetic phenomena that combine elements
of both hereditary and nonhereditary variation and
here is solved (Tikhodeyev, 2012, 2015); the notion of
the term “genotype” is clarified (Tikhodeyev, 2012);
mutational and combinative variability are clearly
delineated and a modern classification of mutations is
proposed (Tikhodeyev, 2015). The purpose of this
article is to use the differential concept of variability to
clarify the notion of the term “epigenetics.”
A BRIEF HISTORY OF THE TERM
“EPIGENETICS”
The term “epigenetics” has been suggested by
Waddington in the 1940s (Waddington, 1942), when
virtually nothing was known about the nature and
mechanisms of gene action. In particular, it was com-
pletely unclear what processes provide organism
development and thereby underlie phenotype estab-
lishment. The study of these processes, according to
Waddington, represented a strategically important
task, especially given the fact that the phenotype is not
always clearly defined by the genotype, i.e., can
exhibit high plasticity. The term “epigenetics” was
introduced exactly to refer these studies.
The etymology of this term is quite complicated
and therefore needs special explanation. As early as IV
BC, Aristotle articulated the idea that an organism
develops through gradual and qualitative changes in
embryo structures. Much later, in the middle of the
17th century, such processes were called epigenesis,
and since then this word was incorporated in biologi-
cal vocabulary (Haig, 2004). However, along with the
ideas of epigenesis, there was an alternative point of
view called “preformation.” In accordance with this
concept, the structure of an adult organism is rigidly
predetermined in the embryo (Dondua, 2004). Wad-
dington believed that individual development imple-
ments both of the above principles: the general scheme
is originally given by the genotype, while details are
formed through epigenesis, resulting in phenotype
plasticity. He believed that here is the main difference
between genetics and epigenetics: genetics studies the
determining effect of genes and epigenetics investi-
gates mechanisms of epigenesis (Waddington, 1956).
Waddington’s view on spontaneous plasticity of the
phenotype was so revolutionary for biologists that it
was marginalized for a long time. Therefore, the term
“epigenetics” was rarely used prior to the early 1990s.
However, there was growing evidence that the process
of individual development is indeed complex and does
not depend only on the genotype. As a result, starting
from the first half of the 1990s, this term was used in
descriptions of various developmental phenomena as a
synonym for the entire developmental biology. Finally,
after discovery of hereditary mechanisms, in which the
primary structure of DNA remains intact, this term
became well known but in a very different, molecular
meaning. Thus, the modern understanding of epi-
genetics combines three autonomous aspects of vari-
ability: the origin of arising differences (ontogeny), their
heritability, and their molecular nature. Herein the
essence of the discussed contradictions lies.
Table 1. Distinctive features of mutations and modifications in the context of the integral concept of variability
1
From the modern point of view, there are four such factors: diversity of the initial hereditary material, ontogenetic regularities, direc-
tional environmental influencies, and molecular stochastics (Tikhodeyev, 2013). Accordingly, there are four forms of variability: geno-
typic, developmental, modificational and fluctuational. 2 Obsolete ideas (see Table 2 and explanations in the text). 3 The exposed
objects should be aligned for the genotype and the stage of individual development.
Compared aspects of variability Mutations Modifications
Factors generating variation of pheno-
types1
Stochastic events leading to unpre-
dictable changes in phenotype2
Environmental influences leading to uni-
directional changes in phenotype3
Molecular nature of occurring changes Changes in DNA amount or struc-
ture2
Changes in gene expression without alter-
ation in DNA amount or structure2
Capability of changes to be transmitted
to offspring
Occurring changes are stably inher-
ited
Occurring changes are not inherited2

EPIGENETIC AND EUGENETIC PROCESSES 335
SPECIFICITY OF EPIGENETIC PROCESSES
IN THE DIFFERENTIAL
CONCEPT OF VARIABILITY
Let us go back to abovementioned interpretations
of epigenetics and critically analyze each of them. In
accordance with the first one, epigenetic phenomena
include any heritable alterations of the phenotype not
associated with differences in the primary structure of
DNA. Until recently, it was assumed that the mecha-
nisms of such alteration are very few. However, the real
situation is quite distinct. About a dozen of different
mechanisms underlying this kind of inheritance are
already known (Table 2), and this list is likely to be
expanded. Thus, we can expect that almost any
molecular mechanism involved in gene expression, in
a given set of conditions, can lead to heritable changes.
However, if the necessary conditions are not met, the
corresponding changes will not be inherited.
Multiple facts do indicate that the same epigenetic
alteration in some cases is inherited but in others is
not. Here are just two examples. In Arabidopsis, long-
term cold exposure induces triple methylation of his-
tone H3 at the site of the FLC gene (Henderson et al.,
2003; Kim et al., 2009). This effect is stably inherited
in mitosis, thus persisting in vegetative generations,
but is unable to be transmitted through meiosis (Choi
et al., 2009). The second example is the situation with
prion [PSI+]. This prion occurs in yeast as a result of
the SUP35 protein transition from its normal to amy-
loid conformation (Derkatch et al., 1996). As a rule,
prion [PSI+] is stably inherited both through mitosis,
meiosis and cytoduction, but it is neither reproduced
nor transmitted to progeny under the lack of the
HSP104 gene function (Chernoff et al., 1995). It is
worth adding that this pattern applies to a variety of
other yeast prions (Crow and Li, 2011).
These facts allow us to articulate two important
conclusions. First, epigenetic processes are very
diverse in their molecular mechanisms. Second, they
do not guarantee heritability of the occurring differ-
ences, and this conclusion is additionally confirmed at
the level of common logic. In fact, when considering
epigenetic inheritance, we mean that the word “epi-
genetic” serves as an epithet to the word “inheri-
tance,” i.e., it reflects a certain autonomous aspect.
Thus, the above interpretation is incorrect.
The second interpretation assigns the term “epi-
genetics” to a variety of local changes at the chromatin
level. As we have seen, this view is outdated, since
many epigenetic processes are implemented not at the
transcription stage but at later stages of gene expres-
sion (Table 2). Another reason is as follows. Chroma-
tin is characteristic only for eukaryotes, but then any
epigenetic phenomena should be limited to eukary-
otes. Meanwhile, the idea of epigenes—autoregulated
nucleic structures with alternative modes of expres-
sion, each of which is stable in a number of genera-
tions—was formulated back in the 1970s (Churaev,
1975). This idea was experimentally confirmed in bac-
teria (Gardner et al., 2000; Tchuraev et al., 2000).
Thus, epigenetic phenomena are not limited to chro-
matin organization are not unique to eukaryotes.
The third interpretation describes epigenetic pro-
cesses as regulation of gene expression in ontogeny.
This view is close to the original notion of the term
“epigenetics” (the science that studies mechanisms of
phenotypic plasticity) (Waddington, 1942, 1968) and
therefore may seem quite adequate. Nevertheless,
some details require clarification. First of all, it is nec-
Table 2. Molecular mechanisms that can lead to heritable changes in phenotype without alteration of the primary DNA
structure
Mechanism Examplev Object Reference
Changes in the degree of DNA
methylation
BAL epimutation Arabidopsis thaliana Kakutani et al., 1999
Chemical modification of histones Vernalization Arabidopsis thaliana Bastow et al., 2004
Competition of transcription factors Alternative modes of expres-
sion of lacIcI epigene
E. coli Tchuraev et al., 2000
Suppression of plastid translation
by antibiotics
Maternally inherited albino
phenocopies
Nicotiana tabacum, Brassica
napus
Zubko and Day, 1998
Post-translational protein modifi-
cation
Prion C Podospora anserina Kicka et al., 2006
Changes in protein primary structure Prion [β+] Saccharomyces cerevisiae Roberts and Wickner, 2003
Changes in protein tertiary structure Prion [PSI+] Saccharomyces cerevisiae Derkatch et al., 1996
Changes in protein quaternary
structure
Prion [GAR+] Saccharomyces cerevisiae BrownandLindquist,2009
Changes in orientation of cell
organelles
Inheritance of cortex structure Paramecium sp. Beisson, 2008

336
TIKHODEYEV
essary to elucidate what exactly is meant under gene
expression. This term is used too broadly. Formal
genetics interprets it as expression of genes in the form
of specific traits (Aref’ev and Lisovenko, 1995; Patru-
shev, 2000), while molecular genetics refers to synthe-
sis of gene products (Berg et al., 2002; Watson et al.,
2003). This situation often leads to a contradiction: a
gene is expressed from the molecular point of view
(the gene product is synthesized), but it is not
expressed in the formal genetic view (no manifesta-
tions of the specific trait are observed since the gene
product is inactive or degrades). Here is a typical prob-
lem of the integral concept: the same term attempts to
convey two very different genetic notions.
Obviously, these meanings should be separated and
each of them requires a separate term. To solve this
problem, it is not necessary to introduce any new terms:
it is enough to clearly delineate the terms “gene mani-
festation” and “gene expression.” The first refers to
phenomenology, and the second concerns the process
of gene product biosynthesis. Accordingly, the term
“gene expression” has a purely molecular meaning.
The second clarification concerns the question as
to what steps of gene product synthesis are related to
gene expression and why. Here, there is also no single
opinion. Many molecular biologists believe that gene
expression is limited to RNA synthesis (Kapushesky et
al., 2012). However, in this case, gene expression
appears to be identical to transcription, and one of
these terms is unnecessary. To avoid this confusion,
gene expression also includes maturation of tran-
scripts. This interpretation seems to be quite adequate
if the gene product is RNA, but it is not convincing for
other products. Really, if the gene product is a protein,
why its synthesis and maturation cannot be considered
as gene expression? As a result, the most relevant point
of view is that the term “gene expression” covers all
molecular processes providing synthesis of mature
gene products (Berg et al., 2002; Orphanides and
Reinberg, 2002; Watson et al., 2003).
The third clarification concerns regulation of gene
expression. Regulation takes place at different levels,
including primary structure of DNA. Such regulation
may be associated with partial or complete amplifica-
tion of the genome (Gerbi and Urnov, 1996, Tower,
2004), programmed loss of individual chromosomes
(Goday and Esteban, 2001), local genomic rearrange-
ments (Donelson, 2003; Haraldsen and Sonenshein,
2003; Betermier, 2004; Grishanin et al., 2006; Xu et
al., 2012), etc. Should we consider these processes as
epigenetic? Some authors believe that this is possible,
since each of the above mechanisms events is involved
in development (Holliday, 1994; Korochkin, 2006).
Meanwhile, according to many molecular biologists,
these processes are not epigenetic, because they alter
the primary structure of DNA.
Here we again face a mixture of two different
meanings. From the one hand, epigenetic processes
refer to any mechanisms of ontogeny, irrespective to
their molecular nature; from the other hand, they are
understood as specific molecular events regardless of
their biological functions. The first point of view is too
vague, since almost all molecular processes, including
those triggered by environmental factors or some
purely stochastic events, directly or indirectly affect
the ontogeny. The second, in contrast, is quite specific
and therefore much more preferable. In accordance
with this interpretation, the specificity of epigenetic
processes lies in their molecular nature.
Now, based on our analysis, it is necessary to come
to an adequate formulation. We have shown that epi-
genetic processes refer to entire regulation of gene
expression without altering either the structure or
amount of DNA; intact DNA amount is very import-
ant, otherwise, various versions of fertilization, loss of
chromosomes, polyploidy, etc. would also fall within
the scope of epigenetics. However, even taking into
account the latter addition, our formulation is still not
sufficiently correct. The fact is that some epigenetic
events lie beyond the regulation of gene expression.
As noted above, gene expression covers any pro-
cesses providing synthesis of functional gene products.
Such processes include transcription, maturation of
various RNAs, translation, and, finally, protein matu-
ration (Berg et al., 2002; Watson et al., 2003). How-
ever, even the presence of a mature gene product does
not guarantee its proper functioning. The fate of the
gene product depends on many details: it is necessary
to deliver it to the place of destination, provide its
desired conformation, timely activate, timely destroy,
etc. Regulation of each of these molecular processes
(for example, under the influence of environmental
factors) also greatly affects the phenotype without
affecting the primary structure and amount of DNA,
which also refers to epigenetic phenomena. Further-
more, the phenotypic plasticity may be based on auto-
regulation mechanisms involving functioning of the
gene product (Tchuraev et al., 2000; Roberts and
Wickner, 2003; Kicka et al., 2006). Thus, under epi-
genetic processes we understand the whole spectrum
of molecular mechanisms that regulate functioning of
genes and gene products without changing the pri-
mary structure and amount of DNA (figure).
WHAT EPIGENETICS IS OPPOSED TO?
According to the tradition going directly from
Waddington, it is assumed that the term “epigenetics”
means “beyond genetics,” “next to genetics.” How-
ever, let us look at a certain example. In yeast and
mold Podospora anserina, about a dozen of inherited
prions are revealed (Kicka et al., 2006; Crow and Li,
2011; Saupe, 2011; Liebman and Chernoff, 2012). All
of them have an epigenetic nature, but, at the same
time, they provide hereditary traits and therefore
belong to the components of the genotype. Indeed, in
yeast genetics, description of the strain genotype spec-

ifies the presence or absence of specific prions. For
example, the genotype [PSI+
] MATa ade1-14 lys2-29
is typical to the strain 1G-D393 (Kulikov et al., 2001).
As we can see, the same molecular structure is equally
considered as both genetic and epigenetic. The first of
these epithets means that the structure refers to hered-
itary material and the second clarifies its molecular
nature. Thus, the term “genetics” and “epigenetics”
are in a hierarchical relationship with each other (the
first is wider, the second is more narrow) and cannot
be regarded as antagonists.
To find an adequate antonym to the term “epi-
genetics,” let us again turn to the figure. It schemati-
cally represents molecular processes that provide a
pathway from DNA to phenotype. This pathway is not
strictly predetermined: starting from the same initial
DNA, one can eventually obtain different phenotypes.
This situation is caused by two mechanisms. First,
random or regular changes in the primary structure
and amount of DNA may occur in ontogeny of a par-
ticular individual. Second, functioning of genes and
gene products is under complex epigenetic control.
Obviously, this contrast answers the question we
asked. An adequate antonym to the term “epigenetics”
should cover all molecular processes that alter the pri-
mary structure or amount of DNA (Table 3). Such
processes do not yet have a common name. We pro-
pose to call them eugenetic and to consider the corre-
sponding domain of genetics as eugenetics.
The introduction of these terms into the genetic
lexicon creates a logical and clear picture: the pro-
cesses underlying the phenotypic plasticity are divided
into eugenetic and epigenetic. The same can be said
about the mechanisms of inheritance. Eugenetic and
epigenetic inheritance sharply differ in their molecular
nature, but they can lead to the same phenomenology
due to autonomy of different aspects of variability
(Table 4).
This division successfully solves the long-lasting
question regarding genetic information: where is it and
what is it represented with? Earlier, there were two
competing points of view: traditional (only in DNA
molecules and exclusively with nitrogenous bases
sequences; Korochkin, 2006) and innovative (in any
hereditary factor regardless of its molecular nature;
Churaev 2010; Lederberg, 2001; Chernoff, 2001;
Chadov 2006; Inge-Vechtomov, 2013). Now there is
no contradiction between them. There are two forms
of genetic information, eugenetic and epigenetic, and
each of them has its own molecular specificity and
mechanisms affecting the phenotype. Accordingly,
the genotype of any organism consists of eugenotype
and epigenotype (Table 5).
Eugenetic and epigenetic processes not only affect
the phenotype together; they can induce each other in
Processes that underlie phenotype establishment. DNA is understood as initial set of deoxyribonucleic molecules characteristic
of a single cell structure (zygote, unfertilized egg, spore, etc.), the organism begins its development with. Ontogeny implies ran-
dom or regular changes in the primary structure and amount of DNA. 1, regulation of gene expression by altering the primary
structure or amount of DNA; 2, regulation of synthesis and maturation of gene products; 3, regulation of mature gene products
functioning through their transport, folding, activation, degradation, etc.; 4, autoregulation of mature gene products with partic-
ipation of their function. Gray color indicates epigenetic processes; they can be caused by directional environmental influences,
ontogenetic regularities, or molecular stochastics. For other explanations, see the text.
DNA PHENOTYPE
Functioning of genes and their products
1 2 3 4
Molecular
stochastics
Regulation of functioning
of genes and their products
Ontogenetic
regularities
Directional
environmental
inﬂuences
Gene
products
functioning
Provision
of gene products
functioning
Gene
expression
Changes in
the primary structure
or amount of DNA

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TIKHODEYEV
Table 4. Examples of eugenetic and epigenetic changes with similar phenomenology
Phenomenology Examples of eugenetic changes Example of epigenetic changes
Stable Mendelian inheritance Point mutations in yeast LYS2 gene (Kulikov
et al., 2001)
Hypomethylation state of genome regions in
Arabidopsis (Kakutani et al., 1999)
Stable cytoplasmic inheritanc Point mutations in mitochondrial DNA
(Kvitko and Zakharov, 2012)
Prion [PIN+
] in yeast (Derkatch et al., 2001)
Stable asexual inheritance Reconstructions of the major complex of tis-
sue histocompatibility in mammalian lym-
phocytes (Saupe, 2011)
Trimethylation of histone H3 at the site of
FLC gene in Arabidopsis (Bastow et al., 2004)
Reversible noninherited change Repairable premutational DNA changes in
yeast locus MAT (Inge-Vechtomov and
Repnevskaya, 1989);
Effect of jasmonic acids on expression of
genes responsible for defense responses in
plants (Heil and Ton, 2008)
Modificational change CompleteeliminationofmitochondrialDNA
in yeast under prolonged exposure to ethid-
ium bromide (Barclay et al., 2001)
Elimination of prion [PSI+
] in yeast under
prolonged exposure to guanidine hydrochlo-
ride (Wickner et al., 1999)
Ontogenetic change Programmed loss of chromosomes during
embryogenesis in sciarid flies (Goday and
Esteban, 2001)
Regular inactivation of paternal X-chromo-
some during embryogenesis in female marsu-
pials (Gribnau and Grootegoed, 2012)
Fluctuational change Transposon migrations induced by γradiation
in Drosophila (Zabanov et al., 1995)
Random inactivation of one X-chromosome
during embryogenesis in female mice (Clerc
and Avner, 2011)
Table 3. Processes that alter the primary structure or amount of DNA
* Insertion of a noncomplementary nucleotide in the growing chain, alkylation or loss of a nitrogenous base, emergence of a pyrimidine
dimer, etc. DNA methylation (demethylation) does not belong to this group of processes, since it does not cause point mutations or
replication arrest.
Process Character of occurring changes
DNA replication Changes in the primary structure of the growing chain; increasing
number of DNA molecules
Occurrence of double-stranded breaks in DNA Fragmentation of DNA molecules
Occurrence of premutational states in DNA* Changes in the primary structure of DNA that can lead to point
mutations or replication arrest
DNA repair Changes in the primary structure of DNA compared with arisen
premutational states
Occurrence of point mutations Replacement, insertion or loss of base pairs in the DNA molecule
Molecular recombination
Migration of transposons
Occurrence of breaks in the primary structure of DNA, followed by
reconnection of chains
Segregation of DNA molecules during cell division Decrease of DNA molecules amount
Loss of individual chromosomes or plasmids
Nucleus evacuation
Sexual process and its analogs in prokaryotes Increase of DNA molecules amount
Polyploidy
Transformation by DNA molecules
Increase of DNA molecules amount
Reverse transcription

some instances. Eugenetic mutations leading to
hypomethylation of genomic DNA are known in
plants (Kakutani et al., 1999; Woo et al., 2007; Kim
et al., 2008; Hu et al., 2014), and deacetylation of his-
tones H3 and H4 in embryogenesis of sciarid flies
males leads to paternal chromosomes loss (Goday and
Esteban, 2001). However, there is no strong associa-
tion between these processes. In particular, deacetyla-
tion of the mentioned histones in sciarid flies leads to
elimination of chromosomes (Goday and Esteban,
2001), while in plants it induces only transcription
suppression (Liu et al., 2014). Thus, eu- and epigene-
tic processes are autonomous from each other and
should be considered separately.
CONCLUSIONS
One of the most important elements of any science
is corresponding terminological apparatus. Ideally, it
should be clear and consistent. The consistency of the
Table 5. Notion of some genetic terms after introduction of the term “eugenetic processes”
1 Semantically closely related terms (“epinucleic and extranucleic information”) were proposed by Lederberg in the middle of the last
century (Lederberg, 1958). 2
This term is as old as epigenetics. Originally, it meant development processes that lie between genotype
and phenotype (Waddington, 1942). Various interpretations that take into account only regulation at the transcriptional level have
appeared later (Churaev, 1975, 2010; Holliday, 2005; Minarovits, 2006; Whitelaw and Whitelaw, 2006). Our definition, in contrast to
those proposed previously, covers the entire diversity of epigenetic events. 3
In the previous paper (Tikhodeyev, 2015) such mutations
were called genetic; in this article, we correct this inaccuracy.
Concept Interpretation
Molecular genetic processes Molecular processes underlying formation and inheritance of traits
Eugenetic processes Molecular processes that alter the primary structure or amount of DNA
Functioning of genes and gene
products
General molecular mechanisms providing gene expression and functioning of gene
products
Epigenetic processes Molecular processes which regulate functioning of genes and gene products without
changing the primary structure and amount of DNA
Genetics Study of regularities underlying formation and inheritance of traits
Eugenetics A domain of molecular genetics that studies the role of eugenetic processes in formation
and inheritance of traits
Epigenetics A domain of molecular genetics that studies the role of epigenetic processes in forma-
tion and inheritance of traits
Genetic information Information contained in the molecular structures of an organism and used in the its
phenotype establishment
Eugenetic information Information contained in the primary structure of DNA molecules taking in account
their amount
Epigenetic information1 Information contained in the molecular structures of an organism and having an epi-
genetic nature
Genotype All initial hereditary material of an organism
Eugenotype All initial hereditary material of an organism presented in the form of DNA primary
structures
Epigenotype2 All initial hereditary material of an organism with epigenetic nature
Local derivative of genotype All hereditary factors of an organism that have got altered during ontogeny
Local derivative of eugenotype All eugenetic hereditary factors of an organism that have got altered during ontogeny
Local derivative of epigenotype All epigenetic hereditary factors of an organism that have got altered during ontogeny
Mutation Any phenotypic nonrecombinatorial change capable for stable inheritance in generations
(in case of somatic localization—stable asexual inheritance)
Eugenetic mutation3 Mutation caused by a change in the primary structure or amount of DNA
Epigenetic mutation Mutation that is not associated with a change in the primary structure or amount of DNA
Norm of reaction All variety of manifestations of a particular eugenotype taking into account all possible epi-
genetic processes

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TIKHODEYEV
terminological apparatus indicates that the theory is in
good agreement with empirical data and does not
require (yet) any adjustments. However, if accumula-
tion of empirical data makes many key terms vague, it
means that the theory should be reviewed.
This is precisely the situation in genetics at the end
of the 20th–beginning of the 21st century. It became
clear that the same phenomenology may be provided
by different molecular mechanisms, and, on the other
hand, the same molecular mechanism may lead to dif-
ferent phenomenology (Inge-Vechtomov, 2010a; Tik-
hodeyev, 2012, 2013, 2015). Many genetic terms
became fuzzy. This problem was outlined in the 1970s,
but it became particularly acute in recent decades due
to epigenetic inheritance discovery. It is not surprising
that an urgent, sometimes irreconcilable controversy
has arisen around the term “epigenetics.”
On the one hand, a number of molecular phenom-
ena (prions, genomic imprinting, etc.) did not fit into
traditional genetic concepts and therefore needed a
new terminology. In this regard, the use of the term
“epigenetics” seemed quite logical and reasonable. On
the other hand, there were no clear criteria to distin-
guish epigenetic processes. Finally, many old-school
biologists considered this term as misunderstanding,
and this raised additional confusion in genetic lexicon
(Lederberg, 2001).
We have shown that ambiguity of the genetic termi-
nology arises from mistakes of the integral concept of
variability that was established in the early 20th cen-
tury. The solution is to revise the theory: to transit
from the integral concept to differential (Tikhodeyev,
2012, 2013, 2015). In this paper, we used the differen-
tial concept to reveal specificity of epigenetic pro-
cesses.
This specificity is based on three details. First, only
molecular mechanisms which provide functioning of
genes and gene products are mentioned. Second, epi-
genetic processes do not disrupt the primary structure
or amount of DNA. And third, the same molecular
change in some cases is inherited, however, in others
not. Thus, epigenetic processes refer to the whole
diversity of molecular mechanisms that regulate func-
tioning of genes and gene products without changing
the primary structure and amount of DNA.
It is easy to note that our definition successfully
combines the most important elements from the pre-
vious interpretations of the term “epigenetics.” Like
Waddington, we consider molecular processes that
directly provide phenotypic plasticity. The new defini-
tion covers most of molecular mechanisms involved in
regulation of gene expression, including local changes
at the chromatin level. Epigenetic phenomena are
clearly distinguished from changes in the primary
structure and amount of DNA (i.e., from eugenetic
processes). The new definition also allows epigenetic
inheritance.
The latter detail requires special attention. In
accordance with the differential concept of variability,
the ability of differences to be transmitted from ances-
tors to descendants is independent of their particular
molecular nature. This means that, in principle, any
molecular change under certain conditions can be
inherited. This view is consistent with a variety of epi-
genetic inheritance mechanisms discovered in the past
two decades (Table 2). It is likely that in the near future
this list will be substantially expanded. Furthermore,
some unexpected phenomena may become a part of
epigenetic processes. Imprinting of wedding songs in
finches is a good example: a young male remembers a
wedding song heard within a strictly defined period of
development and sings only it as an adult (Adret,
1993). Here is, in fact, typical epigenetic inheritance:
a trait can be transmitted in a number of generations
independently of the primary structure and amount of
DNA. The transmission mechanism is still unclear,
but it seems to be closely related to the regulatory pro-
cesses that occur in the brain neural structures as a
result of exposure to a specific external stimulus. Let
us note that the same wedding song, depending on the
stage of development of the young male, is inherited in
some cases, but in others is not. It fits perfectly into
our concept of variability. The only difference from
the true epigenetics is that the trait can be transmitted
not only to direct biological descendants but also to
other representatives of the same or closely related
species. It is likely that approximately the same logic
applies to the entire signal heredity in general.
So, using the differential concept of variability, we
have saved the term “epigenetics” from ambiguity and
found its adequate place in the genetic lexicon. Thus,
we have made one more important step towards creat-
ing a new, modern genetic theory that equally covers
both traditional regularities and the newly discovered
noncanonical phenomena: protein heredity, genomic
imprinting, etc.
ACKNOWLEDGMENTS
This work was supported by a grant from St. Peters-
burg State University, no. 0.38.518.2013, and a grant
from the Russian Foundation for Basic Research,
no. 15-04-05579.
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