ISSN 20790864, Biology Bulletin Reviews, 2015, Vol. 5, No. 2, pp. 119129. Pleiades Publishing, Ltd., 2015.

Original Russian Text O.N. Tikhodeyev, 2014, published in Uspekhi Sovremennoi Biologii, 2014, Vol. 134, No. 4, pp. 350362.

Crisis of the Term Mutation and Its Resolution

in the Context of the Differential Concept of Variability
O. N. Tikhodeyev
St. Petersburg State University, Universitetskaya nab. 7/9,
St. Petersburg, 199034 Russia
email: tikhodeyev@mail.ru

AbstractThe traditional views on mutations are critically analyzed. It is shown that in modern genetics, the
term mutation is used inadequately, covering an overly wide range of phenomena. We propose a strict defini
tion of this term, which allows clear distinguishing mutations from all other variability manifestations. The
main approaches to classify mutations are discussed. The meaning of the term combinatorial variability is
also specified.

Keywords: mutational variability, combinatorial variability, term mutation, classification of mutations, for
mal recombination, molecular recombination, differential concept of variability
DOI: 10.1134/S2079086415020103

INTRODUCTION makes it possible to resolve numerous contradictions

Any science during the process of its development
inevitably comes to the need for a paradigm shift
(Kuhn, 1973). Such a need is already brewing in mod
ern genetics. It became clear that the traditional con
cepts of variability established in the early 20th century
are full of contradictions and requires serious revision
(IngeVechtomov, 2010a). We have shown that these
contradictions arise from the initially wrong idea that
several aspects of variability which are most important
for geneticists (the heritability of differences, their
molecular nature and the factors determining these
differences) tightly correlate with each other. In fact,
each of these aspects is sufficiently autonomous and
should be considered separately (Tikhodeyev, 2012,
2013).
According to the former concept of variability, any
genetic term successfully covers all of these aspects
simultaneously. For example, modifications were
described as phenotypic differences, which first, are
not transmitted to progeny, second, are associated
with changes in gene expression and third, are deter
mined by environmental conditions. However, this
interpretation was incorrect: some modifications are
stably inherited (Genermont, 1970; Dix, 1977; Cher
noff, 2001; Henderson et al., 2003), and some are
associated with changes in DNA structure (Inge
Vechtomov and Repnevskaya, 1989). As a result, a
serious terminological problem has emerged (Inge
Vechtomov, 2007): what phenomena should be con
sidered as modifications and why?
The new concept, in contrast to the traditional
one, considers every aspect separately from the others
and uses separate terminology for each of them. This
that are typical for modern genetic language. For
example, let us return to the term modification. In
the new concept, it covers only those changes that are
caused by directional environmental influences, with
out regard to heritability and molecular nature
(Tikhodeyev, 2013). This interpretation is much more
successful than the classical one, in which different
aspects of variability were mixed.
Currently, the main advantages of the new concept
are as follows:
1. Three principles to classify variability are clearly
distinguished (Tikhodeyev, 2012)
by ability of changes to be transmitted to progeny;
by factors that determine the variation of pheno
types; and
by molecular nature of occurring changes;
2. The problem of numerous genetic events that
combine elements of hereditary and nonhereditary
variability and thus do not fit the traditional concept is
solved (Tikhodeyev, 2012). We have shown that instead
of the integral parameter heritability, at least three
autonomous parameters should be used: the ability of
a change to be inherited in asexual reproduction, the
ability of a change to be inherited in sexual reproduc
tion, and, finally, the steadiness of the given change.
Thus, a more detailed classification was proposed,
which covers all manifestations of variability (Table 1);
3. The factors determining the variation of pheno
types are clearly distinguished (Tikhodeyev, 2013). It
was shown that there are four such factors: genotype,
stage of development, directional environmental
influences, and molecular stochastics. Accordingly,

119
120 TIKHODEYEV

Table 1. A variety of genetic events classified according to the stability of the changes and their ability to derive sexually and
asexually
Analyzed aspects of changes
ability to be inherited Examples of genetic events
steadiness1
sexually asexually
High + + Generative mutations;
recombination in germ cells and their analogues2;
steady genotrophy3;
steady paramutations4
Low + + Gradually declining genotrophy;
gradually declining paramutations
High + Mutations and recombination in agamic species;
somatic mutations;
recombination in somatic cells and their analogues5;
steady dauermodifications
Low + Gradually declining dauermodifications
High Phenocopies;
terminal differentiation;
dominant lethals
Low Adaptive modifications;
phenotypic suppression
1Compared
to the first publication (Tikhodeyev, 2012), in this paper, the formulation of one of the analyzed aspects is clarified. Instead
of the wording stability of changes, we use a more appropriate wording steadiness of change (steady changes do not decline after
the lack of inducing factor, but can revert; i.e., can be unstable). 2 For example, in ciliate micronuclei. 3 Genotrophy is the induction of
heritable changes by nonmutagenic environmental factors, such as modified mineral nutrition (Durrant, 1971), nicotinic acid
(Bogdanova et al., 2009) or Triton X100 (Makhmudova et al., 2012). Steady genotrophy is per se identical to mutations and has differ
ent referrence only because it is induced by environmental factors of a nonmutagenic nature. 4 Paramutations are changes in allele
manifestation occurring after heterozygous state (Brink, 1958; ArteagaVazquez and Chandler, 2010). Such changes usually decline in
further generations, but sometimes appear to be steady. 5 For example, in ciliate macronuclei.

four types of variability were identified: genotypic,
ontogenetic, modificational, and fluctuational;
4. The term genotype was defined more accu
rately (Tikhodeyev, 2013). It was shown that genotype
should be defined as the set of initial hereditary factors
of an organism regardless of their molecular nature.
The term local genotype derivatives, which covers
any (including shortterm) changes in hereditary fac
tors during ontogenesis, was introduced. These speci
fications allow a clear distinction between the geno
typic and ontogenetic variability, which was impossi
ble under the traditional concept;
5. A clear definition of the term modification
was given (Tikhodeyev, 2013);
6. The general biological essence of noncanoni
cal phenomena, such as incomplete penetrance,
varying expressivity, and fluctuating asymmetry, was
revealed, and their place in the new classification of
variability was shown (Tikhodeyev, 2013).
Comparing the old and the new concept, we sup
pose that the main differences between them can be
formulated as follows. The former concept, in fact,
was integral (different aspects of variability were
thought to be closely related and were described by the
same terminology). The new concept is differential
(different aspects of variability are autonomous, and
each of them requires its own terminology). We believe
that these epithets are sufficiently convenient and will
use them in the sequel.
In this paper, the differential concept of variability
is used to answer the urgent question: what are muta
tions, and how to classify them?
WHAT IS CALLED MUTATIONS?
The term mutation is one of the most important in
genetics. Nevertheless, so far in the scientific literature
there is no generally accepted interpretation of this term,
and in different cases it is used in different ways. Let us
briefly examine the reasons for this situation.
In the early 20th century, it seemed obvious that
genetics, with its discrete hereditary factors, is funda
mentally contrary to the theory of natural selection,
according to which the main evolutionary role is
played by small, seemingly invisible hereditary differ
ences (Gaisinovich, 1988). In this regard, new evolu
tionary concepts have been coined as a replacement
for outdated Darwinism. One example of such con
cepts is the mutation theory by de Vries. It postulated
that the evolutionary process is based on sudden salta

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 CRISIS OF THE TERM MUTATION AND ITS RESOLUTION
tory changes in traits. These changes can be stably
retained in further generations and lead directly to
new elementary species (de Vries, 1901, 1903). The
term mutation was introduced to define exactly
such changes. Thus, its initial interpretation was
mostly evolutionary rather than genetic.
Further development of genetics showed that single
mutations do not lead to speciation, and de Vries him
self worked with varieties but not with species (Allen,
1969). So, the original interpretation of mutation
very soon lost its evolutionary meaning. Its genetic
meaning has also gradually changed. First, genetics
has come to the conclusion that hereditary traits are
determined by hereditary factors and these notions
should be clearly distinguished (Johannsen, 1909).
Second, it was found that hereditary changes are
caused not only by mutations but also recombinations
(Morgan, 1911; Muller, 1916). As a result, hereditary
variability was subdivided into mutational and combi
natorial, and the meaning of mutation was recom
prehenced as a sudden change in hereditary factors
unrelated to the sexual process and crossingover.
Since the molecular nature of heredity was
unknown up to the middle of 20th century, the nature
of mutations also remained unclear. Nevertheless, it
was shown that various mutations differ in the degree
of genetic material change: some of them affect a sin
gle gene and are not detected by cytogenetic methods,
whereas others are associated with more pronounced
disturbances altering the structure or the number of
chromosomes (Lutz, 1907; Bridges, 1922, 1923;
Karpechenko, 1927). So, mutations were subdivided
in two classes: gene mutations and chromosome muta
tions. For different chromosome mutations, special
terminology was often used (chromosome rearrange
ments and chromosome number changes), while gene
mutations were regarded as true mutations. Thus, a
mutation in the strict sense of the word was considered
as a sudden change in a gene.
After proving the genetic role of DNA (Avery et al.,
1944; Hershey and Chase, 1952; Watson and Crick,
1953), the term mutation became associated with a
change in the structure or the number of deoxyribonu
cleic molecules. It turned out that these changes are
highly diverse. In particular, even real (gene) muta
tions can be caused by different events, such as
intragenic rearrangements, directed conversion,
transposon migration, and DNA polymerase errors
(Auerbach, 1976; Walbot, 2000; Griffiths et al., 2007;
Haber, 2012). The majority of molecular geneticists
believe that only the last type of DNA changes can be
considered as really true mutations. Such mutations
are called point mutations.
Extensive use of comparative genomics methods
has led to the identification of multiple sites of poly
morphism, where nobody knows what is the norm and
what is mutation (The 1000 Genomes, 2010). As a
result, a new molecular trend has emerged: only rare
alleles with a frequency of less than 1% are regarded as
BIOLOGY BULLETIN REVIEWS Vol. 5 No. 2 2015
121
mutations, and the remainder are considered as natu
ral polymorphisms (Twyman, 2003; Dhruve, 2008).
The above misunderstandings were eventually sup
plemented with one more problem. It turned out that
hereditary differences may be determined by a set of
molecular events leading to steady changes in gene
expression without alterations in DNA nucleotide
sequences. Such cases are called epigenetic mutations.
This type of events can be associated with changes in
the methylation degree of nitrogen bases (Kalisz and
Purugganan, 2004), steady chemical modification of
histones (Richards, 2006), competition between dif
ferent transcription factors (Tchuraev, 2005), persis
tent changes in protein conformation (Chernoff,
2001), etc. It should be noted that some epigenetic
mutations are inherited in full compliance with Men
dels laws and even can be localized on genetic maps
by the standard methods of linkage analysis; i.e., they
are outwardly indistinguishable from true mutations
(Kakutani et al., 1999; Manning et al., 2006).
Thus, during its more than centenary history, the
term mutation has repeatedly changed its meaning.
Initially, it reflected phenomenology only, but later it
was filled with genetic mechanisms and eventually has
acquired a molecular tinge. However, it should be
taken into account that many mutations have not yet
been studied from the molecular point of view. Such
mutations are described in the oldfashioned man
ner, i.e., solely by their phenomenology. So, in the
modern scientific literature, different notions of
mutation can be found, starting with classical and
ending with pure molecular ones (Table 2).
TRADITIONAL FEATURES OF MUTATIONS
It is quite obvious that in different definitions of
mutation, the main attention is paid to different
details. So, the principal question comes up: are there
any features peculiar to all phenomena referred as
mutations?
When discussing the distinctive features of muta
tions, the majority of modern geneticists (Auerbach,
1976; Ayala and Kiger, 1984; Zhimulev, 2003; Griffiths
et al., 2007; IngeVechtomov, 2010b) agree on the fol
lowing:
1. Mutations occur suddenly and unpredictably;
2. They lead to saltatory changes in phenotype
without continuous series and intermediate forms;
3. Mutational changes are steady;
4. They can be transmitted from ancestors to
descendants;
5. Mutations can arise in any direction;
6. They occur at a low frequency;
7. Mutations are associated with changes in DNA
molecules;
8. The mechanisms of mutations differ from those
of recombination.
122 TIKHODEYEV
Table 2. Diversity of modern interpretations of the term
mutation
Definition of the term
Literature source
mutation
Suddenly occurred heritable Auerbach, 1976 (p. 27)
change
Change in a gene Watson et al., 2004 (p. 15)
Transition of a gene from one Griffiths et al., 2007 (p. 178)
allelic state to another
Chemical change in a gene, Dubinin, 1976 (p. 18)
change in the structure or
number of chromosomes
Change in DNA amount or Ayala and Kiger, 1984 (p. 7)
nucleotide sequence
Heritable change in genetic IngeVechtomov, 2010a
material that cannot be (p. 4)
reduced to the characteristics
of the genetic material (geno
type) of parents
Rare allele with a frequency in Dhruve, 2008 (p. 208)
the population of less than 1%
Let us briefly analyze these statements. First, some
of them overlap. This concerns the sudden nature of
mutations (the statement 1), the unpredictability of
their phenotypic effects (the statement 5), and the low
frequency of such events (the statement 6). These are
different consequences of the stochastic nature of the
mutation process, and so they can be combined into
one. However, it would be wrong to assert that any
mutation is generated by molecular stochastics. In
some cases, clearly predictable mutations were
described, occurring practically in all progeny and
leading to the predetermined outcomes.
Examples of such mutations are the induction of
[rho0] yeast mutants under longterm exposure to
ethidium bromide (Barclay et al., 2001), the elimina
tion of different prions in the same object as a result of
repeated passaging on a medium with guanidine
hydrochloride (Chernoff, 2001), chromatin diminu
tion during ontogenesis in ascarids (Muller and Tobler,
2000), and programmed chromosome losses during
sciarids development (Goday and Esteban, 2001). In
the first two cases, mutations are caused by directional
environmental influences; in the third and fourth
cases, by ontogenetic regularities. Thus, neither the
frequency of the observed changes, nor the degree of
their predictability or their cause relate to the essence
of mutation.
The saltatory effects of mutational changes has
been long believed to be an axiom. However, according
to molecular genetics data, many point mutations are
almost neutral (Kimura, 1983; Hunt et al., 2009) or
lead to extremely weak phenotypic effects that can be
identified only by very sophisticated methods (Mackay,
2001; Barton and Keightley, 2002; Aulchenko and
Aksenovich, 2006). It can be argued that the structure
of the genetic material, for some extent, is also a com
ponent of the phenotype and that any mutation (even
neutral) is therefore already saltatory in its molecular
nature. However, this logic also has serious drawbacks.
The fact is that the process of a point mutation rise is
per se not a saltatory event: it is extended in time and
passes through an intermediate state in the form of a
local mismatch in the DNA (Loeb and Cheng, 1990;
Marnett and Plastaras, 2001). Thus, the statement 2 is
outdated indeed.
Now, consider the statements 3 and 4. It may seem
that they are valid for all mutations; however, there are
exceptions here as well. A very interesting example was
described in yeast. In this object, a set of point muta
tions in the PMA1 gene affecting highly conserved res
idues in the plasma membrane H+ATPase has been
artificially obtained (Portillo and Serrano, 1988; Har
ris et al., 1994). The D378N mutation is worth partic
ular attention. Attempts to transform wildtype cells
with an expressing copy of the gene with this mutation
revealed a very strange pattern: the cells were trans
formed, but all the progeny was normal. It was found
that this mutation leads to nonviability, even in the
presence of a normal allele of the gene, and therefore
cannot be maintained in further generations. The only
way out of this situation is spontaneous conversion of
the mutation. As a result, the cell eliminates the lethal
allele, retains viability, and undergoes further division;
however, in this case, only the normal allele is inher
ited (Harris et al., 1994). Thus, here the D378N muta
tion is neither stable, nor transmittable to the progeny.
Taking into account the significant number of domi
nant lethals occurring in different objects under the
influence of mutagens (Alexander and Stone, 1955;
Ehling, 1971; Vatti and Tikhomirova, 1976; Ivanov,
1998; Nakano et al., 2003), it is likely that such muta
tions are widespread in nature but, for obvious rea
sons, drop out of the analysis.
Consider the statements 7 and 8. The first of them
is no longer relevant after the discovery of protein
hereditary factors and elucidation of the essence of
protein mutagenesis (Wickner et al., 1999; Cher
noff, 2001). The statement 8 is also faulty, because
many gene mutations result from events of a recombi
natory nature: rearrangements (Benzer, 1961; Sher
man et al., 1975), transposon migration (Walbot,
2000), and directed conversion (Haber, 2012).
Thus, if the term mutation is considered in all
diversity of its modern interpretations, it has no clear
distinguishing features (exceptions can be found for
each interpretation). This means that, in the modern
genetic terminology, this term is used inadequately,
covering too wide range of phenomena.
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 CRISIS OF THE TERM MUTATION AND ITS RESOLUTION 123

Table 3. Comparison of formal genetic and molecular views on the term recombination
View on the term recombination Corresponding interpretation Covered genetic events
Formal genetic Emergence of a new combination of old Independent segregation of nonhomol
alleles ogous chromosomes or other carriers of
hereditary factors1; sexual process;
crossingover (as a formalgenetic pro
cess leading to recombination of linked
alleles)
Molecular2 Breaking of DNA strands with their subse Crossingover (as a molecular process);
quent physical ligation conversions; genomic rearrangements;
migration of transposons; integration
and excision of episomes; horizontal
gene transfer
1
For example, different subgenomes in retroviruses or some prions in yeast. 2 In modern molecular biology, the term recombination is
sometimes applied to proteins and RNA in terms of different types of splicing (Lew et al., 1999; Thompson and Herrin, 1994); in this
paper, this term is applicable only to DNA.

THE TERM MUTATION key characteristics of mutations and remain so in the

IN THE DIFFERENTIAL CONCEPT
OF VARIABILITY
The main origin of the vagueness of mutation
lies in attempts to endow this term with two very dif
ferent genetic meanings. The first one was created by
classical genetics at the very beginning of the 20th cen
tury and, therefore, relies entirely on phenomenology
(steadiness of changes, their heritability, etc.) without
any linkage to molecular mechanisms. The second has
appeared almost half a century later, when it became
clear that many gene mutations are caused by single
base pair substitutions, insertions, or deletions in
DNA. As a result, these two meanings were mixed. So,
if such a substitution, insertion, or deletion was iden
tified in a certain DNA molecule, the found distinc
tion was also called a mutation.
At the early stages of molecular genetics develop
ment, such mixing seemed to be quite reasonable.
However, today, taking into account all available data
on unstable and noninherited nucleotide substitutions
and various epigenetic mutations, mixing of these two
meanings is incorrect due to many obvious inconsis
tencies between them. These meanings should be
clearly delineated. We suppose that the term muta
tion applies only to the first meaning, and the second
requires another terminology (see below).
Now, based on the above specifications, let us
return to the list of traditional features of mutations
and perform its critical analysis once again. First of all,
the statement 7 should be rejected (the molecular
nature of mutation is irrelevant). Then, the statements
1, 5, and 6 are also excluded (examples of strictly
directed mutations occurring in all progeny are
known; see above). The statement 2 should also be dis
carded: it is not true for each mutation, especially in
the case of quantitative traits. The statements 3 and 4
are out of doubt. Indeed, the steadiness and transmis
sibility to progeny were originally considered as the
differential concept.
The greatest difficulties are associated with the
statement 8. On the one hand, there is a persistent tra
dition to discriminate between mutational and combi
natorial variability (Filipchenko, 1926; Baur, 1930).
On the other hand, there are numerous examples
where mutations have a recombinatory nature (Ben
zer, 1961; Sherman et al., 1975; Walbot, 2000; Haber,
2012). This contradiction requires special explana
tion.
Despite all advances and possibilities of molecular
genetics, it would be a great mistake to assert that for
mal genetic analysis is now in the past, making way for
genomics, proteomics, etc. The classic and new
approaches are not mutually exclusive. Describing the
same genetic regularities, they draw attention to dif
ferent aspects of variability (formal genetic analysis
focuses on phenomenology, while molecular analysis
reveals the nature of differences). Since there is no
rigid connection between these aspects, two different
descriptions are inevitably obtained, and some terms
have different elucidation in these two discriptions. In
particular, this applies to recombination. This word is
used in two ways. In the molecular notion, it refers to
the break and ligation of DNA strands (Smith, 1987;
Craig, 1988; Bogue and Roth, 1996; Filippo et al.,
2008); in the formal genetic one, it indicates the
appearance of new combinations of preexisting alleles
(Filipchenko, 1926; Baur, 1930). Both interpretations
are directly associated with the emergence of new
combinations of hereditary factors but strongly differ
in the spectrum of covered events (Table 3). Thus, we
deal with two different terms reflecting different
aspects of recombination. Accordingly, we suggest that
the wordings formal recombination and molecular
recombination should be clearly distinguished from
one another, and then the problem can be easily
solved.

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124 TIKHODEYEV
Indeed, mutation is a formal genetic term that is
not linked to molecular mechanisms. Therefore, it is
not surprising that some mutations are caused by
chromosomal rearrangements, directed conversion, or
transposon migration (in other words, by molecular
recombination). Formal recombination only shuffles
the old alleles and cannot lead to new mutations.
Exactly this view on recombination is the base for the
old tradition to distinguish between mutational and com
binatorial variability. Thus, the statement 8 is true but
covers only formal recombination and therefore needs to
be corrected. The above molecular statement, the
mechanisms of mutations differ from those of recombi
nation, should be replaced with the formal genetic one
mutations arise via a noncombinatorial way.
Let us summarize the main results of the analysis.
We have shown that the general properties of all muta
tions are steadiness, transmissibility to progeny, and a
noncombinatorial origin. However, these properties
are insufficient to create an unambiguous definition of
mutation. Indeed, relying on only these features, it
is impossible to clearly distinguish somatic mutations
from another genetic phenomena called steady dauer
modifications. Both emerge via a noncombinatorial
way, are steadily inherited in mitotic generations, and
are not sexually transmitted to progeny (Table 1; see
Genermont, 1970; Dix, 1977; Kaeppler et al., 2000;
Henderson et al., 2003; Miguel and Marum, 2011).
Thus, to make the definition strict, it is necessary to
introduce an additional characteristic allowing clear
discrimination between these events. The case in point
is the localization of changes within the organism. If a
change affects the entire organism but can be inherited
only asexually, then it is lost during meiosis and should
be refered as a dauermodification. If a change is
located in soma, and this is the reason of asexual
inheritance, then we deal with a somatic mutation. As
a result, we get the following definition: mutation is a
noncombinatorial change capable for steady inherit
ance (asexual in case of somatic localization).
CLASSIFICATION OF MUTATIONS
IN THE DIFFERENTIAL CONCEPT
OF VARIABILITY
Any mutation can be described from different
points of view: localization, phenotypic effects, ability
to be expressed in the heterozygote, molecular nature,
etc. (Ayala and Kiger, 1984; Zhimulev, 2002; Inge
Vechtomov, 2010b). These aspects have no strong cor
relation with each other. Thus, to create a unified clas
sification of mutations reflecting all diversity of their
manifestations, types of inheritance, and mechanisms
of origin is a principally impossible task. Each aspect
requires a separate classification. Let us briefly con
sider the most important of them (Table 4).
The partition of mutations into dominantreces
sive and forwardreverse does not need special com
mentit is described in any textbook on general
genetics. We will not focus on these classifications;
however, others require more attention.
Classification of mutations by molecular nature.
The idea that each mutation is necessarily based on a
change in DNA molecules (their number or nucle
otide sequences) became outdated at the end of the
20th century. Mutations of a completely different
nature are known today. They are caused by steady
alterations in gene expression without changes in
DNA structure or amount (Chernoff, 2001; Kalisz
and Purugganan, 2004; Tchuraev, 2005; Richards,
2006; Akimoto et al., 2007). Therefore, we should
mark out between two types of mutationsgenetic
and epigenetic. This idea was expressed repeatedly in
the past, sometimes explicitly but more often implic
itly (Luria, 1960; Cubas et al., 1999; Christoffers,
1999; Chernoff, 2001; Tchuraev, 2005; Manning et al.,
2006; Richards, 2006; Butler, 2009; Robertson and
Wolf, 2012). However, since this idea contradicted the
integral concept of variability, it did not receive wide
acceptance. The differential concept solves this prob
lem and makes it possible to insert this longstanding
idea into the system of general genetics regularities.
We will not consider the diversity of genetic and
epigenetic mutations, since this topic requires special
analysis. Let us focus only on the most important
point. Describing the nature of certain mutational
changes, we have every right to use such terms as
point mutation, nonsense mutation, missense
mutation, frameshift mutation, etc. However, if
exactly the same molecular changes, for whatever rea
son, cannot be steadily inherited, we should call them
differently: transition, transversion, deletion or inser
tion of nucleotides, etc. For example, the nucleotide
substitution D378N in an expressed copy of the PMA1
gene in yeast is a dominant lethal and therefore is not
retained in further generations (Harris et al., 1994). In
this case, the term mutation is not applicable. Such
a change should be called a missense transition.
Classification of mutations by method for obtaining.
In this case, mutations are divided into spontaneous
and induced. This approach is completely traditional
and needs only one small comment. At present, a
number of mutations are known that are induced by
nonmutagenic environmental factors, such as a
drastically changed mineral nutrition (Durrant,
1971), guanidine hydrochloride (Tuite et al., 1981),
5azacytidine (Akimoto et al., 2007), nicotinic acid
(Bogdanova et al., 2009), or Triton X100 (Makhmu
dova et al., 2012). These mutations should be called
genotrophic. Some of them are epigenetic (Chernoff,
2001; Akimoto et al., 2007; Bogdanova et al., 2009),
and some are apparently associated with genomic
rearrangements (Cullis, 2005).
Classification of mutations by direct cause of origin.
Many mutations (both spontaneous and induced) are
the result of stochastic molecular processes and thus
occur as random rare events. However, strictly predict
able mutations are known, arising in accordance with
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 CRISIS OF THE TERM MUTATION AND ITS RESOLUTION 125

Table 4. Key principles of mutations classification

Classification principle Mutation type Note
By method for obtaining Spontaneous Absent
Induced
By direction Forward
Reverse (reversions)
By ability to manifest in heterozygote Dominant
Recessive
By molecular nature Genetic Caused by changes in DNA molecules1 (their number or
nucleotide sequences)
Epigenetic Have another nature
By immediate cause of emergence Fluctuational Caused by molecular stochastics
Ontogenetic Caused by ontogenetic regularities
Modificational Caused by directional environmental influences
2
By localization in the cell Nuclear Affect hereditary factors located in the nucleus
2
Cytoplasmic Affect hereditary factors located in the cytoplasm
(including mitochondria and plastids)
By localization in the body3 Generative Inherited in sexual reproduction
Somatic Not inherited in sexual reproduction
By the presence of visible changes in Gene Indistinguishable by cytogenetic methods
chromosomes4
Chromosomal Well distinguishable by cytogenetic methods
By produced effects Highly diverse Depend on issue consideration features
1 2
RNA molecules in the case of retroviruses. For eukaryotes. With regard to prokaryotes, this classification distinguishes nucleoid and
plasmid mutations. 3 For eukaryotes having somatic and germinal pathways. 4 For nuclear mutations.

Table 5. Differences between mutations and modifications in terms of the integral concept of variability
Compared aspects Mutations Modifications
Cause of changes Internal* Environmental conditions
Direction of changes Unpredictable* Predictable
Pattern of changes Drastic, saltatory* Fluent, with multiple transitional
forms*
Result of changes for an organism Sometimes benefit, sometimes harm Adaptation to environmental condi
tions (benefit)*
Nature of changes Alterations in DNA amount or structure* Alterations in gene expression*
Ability of changes to be transmit The changes are inherited The changes are not inherited*
ted to progeny
Evolutionary role Well pronounced Absent*
* Outdated statements.

ontogenetic regularities (Muller and Tobler, 2000;
Goday and Esteban, 2001) or under specific environ
mental conditions (Tuite et al., 1981; Barclay et al.,
2001). So, mutations should be accordingly subdi
vided into fluctuational, ontogenetic, and modifica
tional. The last variant is particularly noteworthy. It
was long assumed that mutations principally differ
from modifications (Table 5). However, in reality, the
terms mutation and modification reflect different
aspects of variability and can therefore be successfully
combined with each other.
Classification of mutations by their localization in a
cell. The type of inheritance of a certain mutation
depends on where this mutation is localized. This can

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126 TIKHODEYEV
be clearly seen in eukaryotes when comparing nuclear
and cytoplasmic mutations (Zhimulev, 2002; Inge
Vechtomov, 2010b; Kvitko and Zakharov, 2012). This
classification is inapplicable to prokaryotes. Neverthe
less, for the latter, a similar approach can be used when
distinguishing between nucleoid and plasmid mutations.
They also have different localization in the cell, and this
reflects in their inheritance via conjugation (Snyder and
Champness, 2007; Kvitko and Zakharov, 2012).
Classification of mutations by their localization in
an organism. In a number of eukaryotes (primarily cil
iates and higher animals), germinal pathway is clearly
separated from soma. This also affects the type of
mutation inheritance. If a mutation arose in the
embryonic pathway, it is inherited both mitotically and
meiotically. However, if the same mutation occurs in
soma, it is not transmitted to sexual offspring. Accord
ingly, generative and somatic mutations are distin
guished.
For a long time it was erroneously believed that
somatic mutations are not inherited. This view arose
from the tradition to divide variability into hereditary
and nonhereditary, and to adjust all intermediate phe
nomena to this classification. The differential concept
does not have this drawback. It clearly describes the
specificity of somatic mutations and gives them a
strictly adequate place among the variety of genetic
events (Table 1).
Classification of mutations by the presence of visible
changes in chromosomes. The history of this classifica
tion is very intricate. It goes back to the very beginning
of the 20th century, when genetics dealt with eukary
otes only and the single way to analyze the nature of
mutations was to evaluate chromosomes structure and
number. In this situation, it was considered quite nat
ural that gene mutations dramatically differ from
chromosomal ones (Filipchenko, 1926; Morgan,
1926; Baur, 1930).
This view seemed to be particularly close to the
truth in a version of the same classification, where
mutations are subdivided into genic, chromosomal
and genomic (Lobashev, 1967; Auerbach, 1978;
Zhimulev, 2002; IngeVechtomov, 2010b). It was
believed that gene mutations (also called point muta
tions) are due to DNA replication errors, whereas
chromosome mutations are the results of molecular
recombination errors, and genomic mutations are
caused by errors in cell division. However, this hypoth
esis was not confirmed. It was found that some gene
mutations are the results of molecular recombination
events (Benzer, 1961; Sherman et al., 1975; Walbot,
2000; Haber, 2012) and that some are of epigenetic
nature (Cubas et al., 1999; Kakutani et al., 1999;
Manning et al., 2006). So, the initially synonymous
wordings gene mutation and point mutation
gained completely different genetic senses. The
former remained a formal genetic term and is applied
today only to eukaryotes (furthermore, exclusively to
nuclear mutations). The latter has specific molecular
meaning and is used equally for all organisms. Thus, dis
crimination between gene and chromosome mutations
has no direct relation to their nature and reflects only
the cytogenetic aspect of changes. Point mutations do
not fit into this classification (see classification by
molecular nature).
Classification of mutations by produced effects.
Despite widespread use in the scientific literature, this
classification is extremely heterogeneous and can be
considered from different standpoints (Lobashev,
1967; IngeVechtomov, 2010b). Sometimes mutations
are conventionally subdivided into morphological,
physiological, and biochemical. Sometimes attention
is given to certain traits, thus describing sterility muta
tions, resistance mutations, developmental mutations,
auxotrophic mutations, etc. Sometimes it is conve
nient to classify mutations by the type of changes in a
functional molecular product. In this case, gainof
function mutations, lossoffunction mutations,
switchoffunction mutations, etc., are distinguished.
Other variants of this classification are also possible.
CONCLUSIONS
Over the past few decades, the term mutation did
not have a clear definition. This term was used too
widely, being endowed, depending on the context,
either with the formal genetic or molecular sense
sometimes with both of them at the same time. We
have shown that this approach is not promising,
because different molecular events may underlie the
same genetic phenomenology and vice versa: strictly
identical molecular events can cause different genetic
phenomena. An illustrative example is the D378N
transition obtained in the PMA1 gene of yeast. In an
expressed copy of this gene, it cannot be transmitted to
progeny due to its dominant lethal effect. However, in
a nonexpressed copy of this gene, it is absolutely
harmless and is steadily inherited (Harris et al., 1994).
As we see, the same change in DNA in the first case
appears to be a dominant lethal, whereas in the second
case it manifests as a mutation.
Such examples are not unique (Miraglia et al.,
1991; Harris et al., 1994; Anders and Botstein, 2001;
Thompson et al., 2001). Moreover, identical molecu
lar changes in stem and terminally differentiated cells
can differ markedly in their ability to be inherited.
Thus, the knowledge of the nature of a molecular
change does not allow to conclude about its heritabil
ity, because heritability depends on a number of addi
tional factors. Accordingly, the definition of muta
tion should lack any molecular links. This is a formal
genetic term.
When discussing the new interpretation of muta
tion, it is necessary to take into account three key ele
ments. The first is mutations capability of steady
inheritance. The second is the specificity of somatic
mutations inheritance and their distinction from
steady dauermodifications. And the third is the clear
BIOLOGY BULLETIN REVIEWS Vol. 5 No. 2 2015
 CRISIS OF THE TERM MUTATION AND ITS RESOLUTION
formal genetic boundary between mutational and
combinatorial variability. Accordingly, we define
mutation as any noncombinatorial phenotypic change
capable for steady inheritance (asexual in case of
somatic localization). It does not matter what exactly
the change is. It may relate to any characteristic of the
organism, starting with morphology and ending with
the structure of molecules, up to the nucleotide
sequence of genomic DNA, which, as mentioned
above, is also an element of the phenotype.
It is quite obvious that the proposed definition clear
discriminates mutations from all other genetic phe
nomena. It is therefore far superior to the traditional
interpretations (Table 2). In turn, this success became
possible due to the differential concept of variability,
proving its advantages over the integrated concept.
We have considered the most important classifica
tions of mutations. Although some of them partially
overlap, each is sufficiently autonomous. This fact
appears to be an additional confirmation of the differ
ential concept: different aspects of variability are
autonomous, and each of them requires separate clas
sification and terminology.
ACKNOWLEDGMENTS
This study was supported by a Federal SpecialPur
pose Program, project no. 02.740.11.0698), the pro
gram of the President of the Russian Federation for
support of leading scientific schools, a program of
St. Petersburg State University, project no. 0.38.518.2013,
and a program of the Russian Foundation for Basic
Research, project no. 150405579.
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