LOW-INTENSITY-LOW-DOSE-RADIATION INDUCED GENETIC CODE CHANGES ...
Transcript of LOW-INTENSITY-LOW-DOSE-RADIATION INDUCED GENETIC CODE CHANGES ...
LOW-INTENSITY-LOW-DOSE-RADIATION INDUCED
GENETIC CODE CHANGES AND THEIR
CONSEQUENCES
A. Ya. Temkin
Department of Interdisciplinary Studies
Faculty of Engineering
Tel-Aviv University
Ramat-Aviv
Tel-Aviv 69978
Israel
E-mail: [email protected]
September 23, 2001
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ABSTRACT
Low-intensity-low-dose radiation (ionizing and laser light, as well) and isotope
substitutions in chemical groups (adenine, guanine, cytosine and thymine) of the DNA
molecule may cause changes in genetic information carried by a DNA molecule when
no rupture of its polymer chains occurs. It is shown that in such cases the formal
language based on 4-letter alphabet (A-adenine, G-guanine, C-cytosine and T-
thymine) must be replaced by another formal language with more than 4-letters
alphabet (probably with another grammar). Usually the number of letters in the new
alphabet is so large that the use of such a formal language becomes practically
impossible and so it would be desirable to avoid the use of a formal language. By this
reason it is proposed to use with this purpose the general method of the Ch. 7 of the
book [14]. This method allows one to express the physical properties associated with
rotational, vibration and electronic states of the DNA molecule and transitions
between them in terms of the information and the information processing,
correspondingly. Thus, this method is fit for the treatment of low-intensity-low-dose-
radiation and isotope substitution biological effects because all properties of the DNA
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molecule and all processes occurring in this molecule are expressed uniformly in
terms of the information and information processing. The considered distortion of the
genetic information by the low-intensity-low-dose radiation and isotope substitutions
is expected to be an important (maybe the main) mechanism being the basis of their
biological effects.
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INTRODUCTION
In the present paper we consider such kinds of the radiation induced genetic
harm that are consequences not of the DNA strand decay [1], but only of such
"delicate" damage that leads to distortions of the genetic code. This kind of harm
seems to be important at isotope substitution (see, for example, [2-6]) of elements in
adenine, guanine, cytosine and thymine groups of DNA molecules, as well as at low-
intensity-low-dose ionizing particle, gamma-, X-ray, laser light etc. irradiation. Such
distortion of the genetic code even by very low-intensity-low-dose irradiation may
lead to a considerable increase of cases of malignant diseases as well as hereditary
deviations and abnormalities among the following generations' populations. However,
at the same time it may lead to harmful consequences for malicious cells etc., which,
possibly, opens the way to low-intensity-low-dose laser and ionizing radiation
medical treatment [7-10].
GENETIC CONSEQUENCES OF DNA CHEMICAL GROUPS
IDENTITY VIOLATIONS
Let us begin from the consideration of the genetic information change
provoked by substitution of some elements of adenine, guanine, cytosine and thymine
chemical groups of a DNA strand by their isotopes. It is interesting in itself and also
will help to understand how to approach to more complicated case of similar effects
provoked by the low-intensity-low-dose radiation action.
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The genetic information is written on a DNA molecule by 4-letter alphabet of
a formal language. Each letter means one of 4 type chemical group: A denotes
adenine, G denotes guanine, C denotes cytosine and T denotes thymine. It is
supposed that all chemical groups of the same
type are identical.
This simplifying assumption allowed one to obtain extremely important and
impressive results in the study of genome. However, it must be kept in mind that it is
only, so to say, the zero-order approximation to genetic properties of DNA molecules.
For example, what is to be happened if nuclei of a certain part of atoms of a certain
number of these chemical groups be substituted by their isotopes, e. g., p would be
replaced by d in atoms H, i. e., at certain places deuterium will be placed instead
hydrogen? This example shows that our question is not only an abstract theoretical
question, but is connected with a real situation when the light water is replaced by the
heavy water that reaches the DNA in different places substituting hydrogen by
deuterium. An isotope substitution breaks the identity of chemical groups of the same
type remaining, however, their chemical identity unaffected. Now each two chemical
groups are identical when they were not subjected of isotopic substitution or when the
substitution (by the same isotope) was at the same place in each group. As a
consequence one obtains instead only 4-letter alphabet, the one containing more
(maybe much more) letters: the 4 letters existed from the beginning plus letters
representing chemical groups (chemically the same as mentioned above, but isotope
substituted) classified according substituting isotopes and their places in chemical
groups. The information written by this new alphabet forms the new genome.
It is important that the considered effect differs profoundly from the kinetic
isotope effect, well known in many fields of chemistry. The kinetic isotope effect
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depends on the mass and spin of the element that is substituted by its other isotope, it
decreases when the mass number of this element increases. For example, it can be
important for the hydrogen substitution by deuterium, but negligible for the oxygen-
16 substitution by oxygen-18. In distinct, the considered effect produced by the
genetic code change at the isotope substitution does not depend on mass and spin of
substituted and substituting isotopes of a certain element.
Let us consider the simplest example when in a number of thymine groups
CH3 is replaced by CH2D. Denote the corresponding letter TD. Now there is the five-
letter alphabet 5 = {T, TD, A, C, G}. The formal language built on the grounds of this
alphabet will be a new one. The genetic information written on the non-deuterated
DNA molecule by the language with the alphabet 4 = {T, A, C, G} can be rewritten by
the new language with the alphabet 5 = {T, TD, A, C, G}. Then the information
carried by a non-deuterated and deuterated (as it was described) DNA molecule will be
written by the same language with the alphabet 5 = {T, TD, A, C, G}. It allows one to
compare the genetic information in these both cases, and by this way to understand to
what genetic changes leaded this isotope substitution and at what degree these changes
are important. It is correct also, if not the whole DNA molecule is considered, but only
one gene.
Whether a copy obtained by the duplication of a deuterated DNA molecule
could be deuterated? This is a very important question for the genetics. There are two
possibilities: 1) the copy will not be deuterated, in general, and 2) the copy may be
deuterated by the H - D exchange with the original deuterated DNA molecule or the
protoplasm. It is very not probably that in the case (2) the deuterium substitution will
occur namely at the same places of the new DNA molecule than it was on the original
one. In other words, the identity of the initial DNA molecule and its copy in that what
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concerns the isotope substitution places, practically is not accessible. This means, the
genetic information carried by the copy (written by 5-letter-alphabet language) will be
not the same that the one carried by the original molecule. Really, the situation is even
more complicated because the new alphabet may contain more than five letters.
Indeed, the substitution of H by D is a stochastic process and so can occur not only in
CH3 of thymine, but also in other places of thymine and even in other three types of
chemical groups. It creates more than 5 types of groups distinguished from the original
ones and between themselves, which means that the new more than 5 letters alphabet
and, therefore, the new formal language will be created.
In the case (1) the new DNA molecule will not be deuterated and, therefore, all
the following generations of DNA obtained by subsequent duplications will be not
deuterated. However, it is correct only, if in a certain generation of DNA molecule the
isotope exchange with the protoplasm does not occur. Thus, the influence of the
deuteration will be ended at the initial generation. As opposed to this, in the case (2) it
will remain for all generations. It is to expect that the case (2) will be realized when the
protoplasm contains deuterium. For example, drinking the heavy water can create such
a situation.
GENERAL CASE
The chemical identity of deutero-substituted and not substituted groups really
was not used in the written above. As a consequence, the similar consideration would
be valid also in the case of radiation- and photochemical processes occurring with
DNA molecules. It opens a way to the consideration of such "delicate" genetic effects
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of low-intensity-low-dose ionizing radiation or light, when only a number of chemical
groups in a DNA polymer chain were changed, while the polymer chain itself is not
decayed. Such situations may arise in radiation and photobiology. Then ionizing
radiation or light, e. g., laser light, may induce, for example, one atom H abstraction
from CH3 group of thymine in a number of places of a DNA strand. Thymine groups
with CH2 instead CH3will be different from those with CH3. From the point of view of
formal language it will be the same case than the substitution of CH3 by CH2D, and,
therefore, all written above remains valid. Of course, changes that are results of the
formal language changes do not exhaust all changes of the genetic information
produced by this reaction of the H atom abstraction. This means, when one considers
genetic changes produced by irradiation, it is to divide them into those based on the
formal language change and those based on changes of physical and chemical
properties of DNA molecules. Their dependence on the type of radiation, dose and
dose rate may be different. The first type is especially important at low dose and low
dose rate. Indeed, it is enough a few of cases of the chemical group identity breaking to
provoke serious hereditary aberrations of the future generations or such diseases as, for
example, cancer of the irradiated person himself. The realization of different effects,
arising as consequences of the chemical groups' identity breaking, depends essentially
on the value of the information [11-13] carried by the DNA molecule or by its
segments where this identity breaking occured.
The situation is expected to be much more complicated than the described
above, when the identity breaking of chemically identical groups occurs by "labeling"
a certain part of them by nuclear spin inversions or excitations of molecular quantum
levels. In such cases this "labeling" is rapidly changed as function of time (notice that
isotope exchange may also lead to the time dependence of the "labeling"). Under such
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condition the new alphabet must contain an enormous number of letters and the "text",
i. e., the genetic information, would be rapidly changed as function of time. In such a
situation the writing of the genetic information by a certain formal language becomes
impossible. As a consequence of this fact the new question arises: what, in general, is
in such a situation the genetic information, in other words, how this concept can be
defined, and under what conditions this concept is not nonsense? A criterion that this
concept is not nonsense is as follows. Let I0 is the amount of the genetic information
carried by the original DNA double helix, and I is the maximum change of this
information amount provoked by different factors, as it is written above. Let I reaches
its maximum in time . Denote the characteristic time of life of a DNA strand from
its appearance up to its duplication. Then the concept of the genetic information has
meaning, if , or, when this inequality is not fulfilled, if >>. In fact, this
criterion is not enough, and a number of other criteria must be found that take into
account not only the amount, but also different components of the genetic information
and their values. For example, the criterion written above may be fulfilled, but at a
certain segment of the DNA strand, e. g., a certain gene, the local change of the
information would be too large and would reach its maximum in too short time. Then a
gene (or genes) may be distorted or destroyed. The criterion can be rewritten as
follows. Let L denotes a segment of the DNA strand. Then one can introduce local
information amount and its change, as well as the corresponding time necessary to
reach the maximum of this change: I0,L, IL and L, correspondingly. It must consider
the set {L} of all possible segments covering the considered DNA strand, and to
formulate the above written criteria for each L: the concept of the genetic information
has meaning, iff for all L be IL<<I0,L, or, when this inequality is not fulfilled, iff for
all L be L>>. Possibly, there are other criteria that take into account the values of
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information [11-13] carried by segments. However, we have used "iff" because the task
to determine values of different types of genetic information is extremely difficult,
complicated and not clear, and we shall not consider it in this paper. What means "all
possible segments"? It is not arbitrary set of any segments, but that taking into account
their genetic meaning. One possibility is that each segment must be a gene or its part,
or a number of whole genes, but cannot consist of a part of a certain gene and a part of
its neighbor one.
If some factors provoke changes of the information carried by DNA double
helix, as it was explained above, but the criteria written above are satisfied, the concept
of the genetic information is not nonsense and it is to search for a relevant method of
its expression. It is evident that the use of an alphabet expanding simultaneously with a
corresponding change of the formal language grammar would be not practical. It must
search for other methods.
GENERAL METHOD
Physical processes occurring when an excitation propagates through a DNA
molecule can be expressed in terms of information and information processing, as it
was done in the general form in Ch. 7 of the book [14]. In this chapter the method of
the information processing by activated chains of relations (ACR) [ 14, Chs. 1-3] is
applied to the molecular genetics. Try to discuss whether it is fit for the considered
problem.
Each chemical group a of a DNA molecule has a number of quantum states .
Consider a certain chemical group a in a state as a special entity and represent the
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group a not as a chemical group in different states , but as the set . Note that
in the case of isotope substitution labels the considered chemical group substituted at
certain places by certain isotopes; one value of labels this chemical group without
substitution. This pure formal change of notations (which does not affects the meaning)
allows one to apply the method of the book [14] to the considered problem. All such
elements of a DNA molecule form a set . If be ordered [14,
§7.1], it is none other than the source set defined in [14,Ch.1]. If the ordering
throughout the DNA molecule is impossible, it is to divide it into a number of
segments such that each segment could be ordered independently of others [14, Ch. 7].
After the set was ordered the mathematical formalism of [14, Chs. 1-3 and 7]
can be applied to the considered problems. Note that may be not only different
quantum states (vibration, rotational, electronic), but they may be ionized states, states
when one (or more) atom was abstracted from the group, isotope substituted group
etc.. Therefore, the theory of Ch. 7 of the book [14] can be applied to a DNA molecule
subjected of isotope substitution, excitation of its different degrees-of-freedom,
ionization, atom abstraction etc.. In the majority of cases of low-intensity-low-dose
laser irradiation only the excitation of rotations, however, some times (it depends on
photon energy) also excitation of vibrations and electronic levels is to be taken into
account. In the case of low-intensity-low-dose-ionizing-radiation action upon DNA
molecule also the excitation of electronic levels and ionization customarily must be
taken into account.
The theory proposed in [14, Ch.7] leads to the new definition of the gene that
includes not only the information expressed by the genetic code, but also the
information carried by nuclear and electronic motion in DNA molecule. In the book
[14, Ch. 7] the gene defined so is called C-GENE (complete gene). Its part that does
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not include the information written by the genetic code is called S-GENE (soft gene).
The s-gene expresses in terms of the information and information processing the
physical properties and processes on the levels of nuclear and electronic motion of the
DNA molecule. This is comfortable for the consideration the influence on genetics, for
example, the excitation of rotations, vibrations or of electronic levels by the
irradiation.
CONCLUSIONS
In the present paper we consider the role of the genetic
information distortion without DNA molecule
rupture by the low-intensity-low-dose-laser- or ionizing radiation as well as by
isotope substitutions of elements in DNA molecule in biological effects produced by
these factors. It was shown that the approach based on the use of formal languages
could be realistic only for the several simplest cases of isotope substitution. Namely,
when new formal languages with the number of letters in alphabet more then 4, but
not large, should be used instead the usual 4-letters one (A - adenine, G - guanine,
C - cytosine and T - thymine). However, usually the consideration of the isotope
substitution demands the use of formal languages with too large number of letters in
the alphabet that makes the use of this approach practically impossible. For the
consideration of effects created by the irradiation the number of letters in the alphabet
of the relevant formal language may be so large that practically should be consider as
infinite.
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We proposed to use for the treatment of the considered effects the method of
the information representation and processing by DNA molecule described in Ch. 7 of
the book [14], which is based on the corresponding general method of Chs. 1-3 of this
book. This method allows one to express physical properties and processes of a
polymer molecule, e. g., DNA, in terms of the information and information processing.
Then these properties and processes can be included into the common framework with
the genetic information written by the genetic code. As a consequence of this the
concept of gene was extended [14, Ch. 7] so that it includes, in particular, the dynamics
produced by physical processes occurring on the levels of intramolecular nuclear and
electronic motion (transitions between rotational, vibration and electronic states of the
molecule). This representation is fit for the consideration of the genetic information
radiation damage because it is homogeneous and does not demand the "sewing
together" such heterogeneous characteristics as those expressed in terms of the genetic
code and those expressed in terms of physical properties and processes.
Probably, the described mechanism based on the genetic information distortion
is essential for biological effects produced by low-dose-low-dose rate-radiation.
However, it must be taken into account that other physical, biochemical and biological
mechanisms also contribute to these effects and cannot be neglected.
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