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: temkin@eng.tau.ac.il

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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