GENETIC CODE CHANGES INDUCED BY ISOTOPE

SUBSTITUTIONS AND LOW-INTENSITY-LOW-DOSE

RADIATION, THEIR REPRESENTATION AND

CONSEQUENCES

A. Ya. Temkin

Department of Interdisciplinary Studies

Faculty of Engineering

Tel-Aviv University

Ramat-Aviv

Tel-Aviv 69978

Israel

E-mail: temkin@eng.tau.ac.il

January 8, 2002

1

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 even

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) used for genetic information writing must be replaced by another formal

language with more than 4-letters alphabet (probably with another grammar). The

number of letters in the new alphabet may be so large that the use of such a formal

language becomes practically impossible. So it would be desirable to avoid the use of

any formal language, in general, i. e., to express the genetic information by, so to say,

a "no-language" way. By this reason it is proposed to use with this purpose the general

method of the Ch. 7 of the book [20]. This method allows one to express the physical

properties associated with rotational, vibration and electronic quantum states of the

DNA molecule and transitions between them in terms of the information and the

information processing, correspondingly. Thus, this method is fit, in particular, for the

treatment of low-intensity-low-dose-radiation and isotope substitution biological

effects because all properties of the DNA 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 review [1] the DNA strand breaks are considered as only one of possible

mechanisms of genomic instability induced by ionizing radiation. In the present paper

we shall consider another possible mechanism of genomic changes and instability.

This mechanism is originated from the genetic code changes arising at isotope

substitutions (see, for example, [2-9] and references there) of elements in adenine,

guanine, cytosine and thymine bases of DNA molecules, as well as at low-intensity-

low-dose ionizing particle, gamma-, X-ray, laser light etc. irradiation. They arise also

as result of natural processes occurring in any living being even when there is no

external factor such as radiation, isotope substitution etc.. 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 [10-16].

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

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will help to understand how to approach to more complicated case of similar effects

provoked by the low-intensity-low-dose radiation action.

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 for 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 for

deuterium. An isotope substitution breaks the identity of chemical groups of the same

type remaining, however, their chemical identity unaffected. This violation of identity

is displayed, for example, in magnetic field, e. g., 0.3 Oe magnetic field on the surface

of Earth. In this field the splitting of proton's levels is about 0.16 eV, while for the

deuton ones it is about 0.05 eV between states with spin values -1 and +1, and 0.025

eV between states with spin values -1 and 0, or 0 and +1. This fact is especially

important because all living beings on the Earth live in this magnetic field, their living

processes, reproduction and evolution occur under the influence of this field. The

violation of identity of bases by the isotope substitution of H atom for D influences

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these processes. Note that the described effect of magnetic field is not the only one

displaying this identity violation. For example, isotope substitution changes the

selection rules in chemical reactions that because of it occur differently from those

with non-substituted bases. Now, after the described isotope substitution, 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 of this one obtains instead 4-letter alphabet, the one containing more

(maybe much more) letters. They are the 4 letters existed from the beginning (i. e.,

before the substitution) 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

depends on the mass and spin of the element that is substituted for its other isotope, it

decreases when the mass number of this element increases. For example, it can be

important for the hydrogen substitution for deuterium, but negligible for the oxygen-

16 substitution for 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

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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 replication 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

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. The number of letters of

such an alphabet may be enormous. For example, if all possible versions of atom H

substitution for atom D in four types of bases in DNA molecule are taken into account,

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it is necessary to use an alphabet containing more than 500000 letters. It makes the use

of any formal language practically impossible.

In the case (1) the new DNA molecule will not be deuterated and, therefore, all

the following generations of DNA obtained by subsequent replications 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

Violations of identity of chemically identical DNA bases can be created not

only by isotope substitutions, but, for example, by ionization. It is evident that an

ionized base is not identical to those non-ionized. The same is correct for an excited

(electronically, vibrationally or rotationally) base that is non-identical to those non-

excited. As a consequence, the similar consideration would be valid also in the case of

radiation- and photochemical processes occurring with DNA molecules. In particular,

it opens a way to the consideration of such "delicate" genetic effects of low-intensity-

low-dose ionizing radiation or light, when only a number of bases in a DNA polymer

chain were changed, while the polymer chain itself is not broken. 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

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number of places of a DNA strand. Thymine groups with CH2 instead CH3 will be

different from those with CH3. From the point of view of formal language it will be a

case similar to the one of the substitution of CH3 for 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 [17-19] carried by the DNA molecule or by its segments

where this identity breaking occurred.

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

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

8

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 total amount of the genetic

information carried by the original DNA double helix, and I is the maximum change

of the total amount of this information 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 replication. Then the concept of the genetic

information has meaning, if during the time , 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 total 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 to take this effect into account. 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 during the time , or, when this inequality is not fulfilled, iff for all L be

L>>. Possibly, there other criteria can be found which take into account the values of

different kinds of information [17-19] 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

9

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.

Let us indicate some ways of possible influence molecular genetic processes

by processes occurring on the level of molecular quantum states. The realization of the

genetic information usually occurs by chemical reactions. These reactions or, at least, a

part of them occur via activated complex. Among the channels of its decay there are

those of the excitation transfer (to other parts of the DNA molecule, to the

surroundings etc.). If such an excitation transfer was occurred, reactions corresponding

to other (than the excitation transfer) channels of the activated complex decay will be

suppressed. Such an excitation transfer can be increased or provoked also artificially

by a corresponding addition of inhibitors (acceptors of excitations) to protoplasm. By

this way it is possible to suppress completely concrete, chosen by us, reactions

occurring with a certain base at a certain place of DNA molecule. It would produce

effects like the ones of the methilation, but it can be applied to any base, not only to

cytosine. Perhaps, it can open it can open new ways of medical a. o. applications of the

molecular genetics. On the other hand, the transfer of the energy from donors (excited

molecules added to the protoplasm) to a considered part of DNA or mRNA molecules

10

can create an activate complex that in natural conditions should not exist because there

is not necessary amount of the energy. The decay of this complex may open new ways

of the information realization by reactions. The changes of the probabilities of different

channels of the activated complex decay may be also results of changes of electronic

and nuclear spin states by a magnetic field because it may change selection rules.

GENERAL CONCLUSIONS CONCERNING GENETIC INFORMATION AND GENOME

The written above allows one come to very general conclusions concerning

genetic information and genome representation. We have seen that there are situations

when the information carried by a DNA molecule cannot be represented in terms of

formal languages. Each of such situations considered above corresponded to a kind of

direct action changing the DNA structure issued from external factors (some types of

radiation, isotope substitutions etc.). Such situations can be created artificially, but they

arise also naturally at space flights because the irradiation by cosmic rays. It is

especially important that they exist perpetually for the living beings on the surface of

Earth as well as under water because the natural background of the low-intensity

ionizing radiation. It is created by the natural radioactivity of the soil and by cosmic

rays reaching the Earth surface. All the evolution processes occur under this radiation,

so all living beings adapted themselves to its actions. At the same time this radiation is

an important factor provoking spontaneous genetic changes and, therefore, the one of

the evolutionary development. Genetic changes are provoked also by the Sunlight that

is also a part of normal conditions of the life.

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However, the abovementioned problem with the genetic information

representation arises also when there is no external factor provoking directly changes

of DNA molecule structure or state. For example, the realization of genetic information

concerning the nervous system is usually done by nervous pulses, or, more generally,

molecule excitation propagation through nervous of the peripheral nervous system or

of the brain. The thinking, i. e., the information processing by the brain, is done by this

way. The ability itself to think as well as intellectual abilities to different fields are

contained among the genetic information that is realized as it was described. Thus, the

genetic information, in general, cannot be represented in terms of formal languages

even in absence of abovementioned external factors.

As a consequence of it, genome cannot be represented in terms of formal

languages, the information contained in genome can be represented by a certain way

where the concept of language is not defined.

NOT FORMAL LANGUAGES, BUT WHAT INSTEAD?

A GENERAL METHOD OF THE GENETIC INFORMATION

REPRESENTATION

As it is seen from the previous Section, it is very probably that quantum states

(rotational, vibrational and electronic) of a DNA and mRNA molecules as well as

transitions between them influence genetics. With the purpose to approach this

problem and to study the involvement of such states and transitions between them to

molecular genetic processes, it would be desirable to express them in terms of the

information and information processing. Then the whole problem, which begins from

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the information written by genetic code on the DNA chain and continues by internal

molecular quantum states, would be expressed homogeneously in terms of information

and information processing. It was done in the general form in Ch. 7 of the book [20]

on the grounds of information processing by activated chains of relations (ACR) [20,

Chs. 1-3] applied to the molecular genetics. Try to discuss whether it is fit for the

considered problem.

Each chemical group (base) a of a DNA molecule has a number of quantum

states . Consider a certain chemical group (base) a in a state as a special entity

and represent the 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 for 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 [20] to the

considered problem. All such elements of a DNA molecule form a set

. If be ordered [20, §7.1], it is none other than the source set defined in [20,

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

[20, Ch. 7]. After the set was ordered the mathematical formalism of [20, 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 [20] can be applied to

a DNA molecule subjected of isotope substitution, excitation of its different degrees-

of-freedom, ionization, atom abstraction etc.. In the many cases of low-intensity-low-

dose laser irradiation only the excitations of rotations are to be taken into account.

13

However, some times (it depends on photon energy) also excitations of vibrations and

electronic levels are 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 [20, 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

[20, Ch. 7] the gene defined so is called C-GENE (complete gene). Its part that does

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 how these states and

processes influence genetics, for example, for the consideration of genetic changes

induced by the excitation of rotations, vibrations or of electronic levels by radiation.

However, it must be kept in mind that "influence genetics" means "creation inherited

genetic changes". This note must be taken into account at the consideration of each

concrete case. Then one can state that the proposed method expands the concept of

epigenetics (see, for example, [21-24] and references there) and even proposes its

most general definition.

It seems that our consideration is in agreement with review [1], in which is

showed that for the explanation of experimental results it is to suppose the existence of

other mechanisms of the radiation induced genomic instability than the DNA strand

breaks, and even the contribution of epigenetics is considered.

14

CONCLUSIONS

In the present paper we consider the genetic information

distortion arising without DNA molecule rupture at

the isotope substitutions of elements in DNA molecule 4 bases or at the low-intensity-

low-dose-laser- or ionizing radiation, or at the natural processes, for example, in

central and peripheral nervous systems of living beings. 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, even more than 500000, 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. The similar

situation is created also without an external factor (radiation, isotope substitution etc.)

intervention by natural processes inside a living organism. These processes represent

the genetic information realization and their existence itself means non other that the

organism lives.

We proposed to use for the treatment of the genetic information in such cases

the method of the information representation and processing by DNA molecule

described in Ch. 7 of the book [20], which is based on the corresponding general

method of Chs. 1-3 of this book. This method allows one to express physical properties

15

and processes on the level of molecular quantum states of DNA polymer molecule in

terms of the information and information processing. Then these properties and 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 [20, 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 example, 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, in particular, essential for biological effects produced by low-dose-low-dose rate

radiation and for isotope substitutions. 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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