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Über dieses Buch

This volume – like the NATO Advanced Research Workshop on which it is based – addresses the fundamental science that contributes to our understanding of the potential risks from ecological terrorism, i.e. dirty bombs, atomic explosions, intentional release of radionuclides into water or air. Both effects on human health (DNA and systemic effects) and on ecosystems are detailed, with particular focus on environmentally relevant low-dose ranges. The state-of-the-art contributions to the book are authored by leading experts; they tackle the relevant questions from the perspectives of radiation genetics, radiobiology, radioecology, radiation epidemiology and risk assessment.

Inhaltsverzeichnis

Frontmatter

Chapter 1. Hypermutability Associated with Double-Strand Break Repair

Double-strand breaks (DSBs) are the most toxic kind of DNA damage caused by ionizing radiation as well as by a number of other environmental factors and drugs. DSBs lead to gross chromosome rearrangements, genetic disease, and cancer or cell death. However cells can be programmed to generate DSBs in their own DNA. Programmed DSBs are a key element of many biological functions such as meiotic recombination and segregation, adaptive immunity, regulation switches and viral life cycles. Either damage-induced or programmed DSBs should be repaired in order to retain cell viability. Over the last years it has been established that DSB repair can be associated with up to 10,000-fold increase in frequency of base substitutions and small insertions/deletions (indels). This

localized

hypermutability represents additional genotoxic threat as well as a potential for generating rare multiple mutant alleles with high fitness without overloading the rest of the genome with mutations.

Dmitry A. Gordenin

Chapter 2. A Test of Kimura’s Mutation-Rate Conjecture

Mutation is the first of the four great engines of evolution and the prime source of heritable variation in all living and semi-living organisms and their molecular parasites. As a result, the processes and products of mutation have been deeply explored at both the phenomenological and the mechanistic levels for more than a century. There has been notable progress at both levels over the last half century, with the result that the phylogeny of mutation has become fairly well codified, especially the rates and kinds of mutation in as diverse organisms as could be probed. These explorations began to coalesce in the 1990s and soon comprised a small number of broad generalizations. These include very high genomic mutation rates in riboviruses and some higher eukaryotes, and strikingly similar genomic mutation rates in most DNA microbes. However, highly informative exceptions have recently been observed.

John W. Drake

Chapter 3. Micro-algae as a Model System for Studying of Genotype Resistance to Oxidative Stress and Adaptive Response

Here we discuss the possible contribution of DSB DNA repair and chaperone systems for the formation of genotype resistance to oxidative stress and the possible correlation between cells’ genotype resistance and the magnitude of adaptive response (AR). Mutant strains of

Chlamydomonas reinhardtii

showing different levels of gamma- rays, paraquat- and zeocin-resistance as well as species

Chlorella

isolated from habitats with extreme environmental conditions are used as a model system. On the basis of results obtained it could be speculated that genotype resistance to oxidative stress may not always correlate with the initial level of DSB induced, but rather with higher DSB repair capacity and higher content of constitutive HSP70B. Our results concerning the relationship between genotype resistance to oxidative stress and adaptive response confirm our previous suggestion that up-regulated DSB DNA rejoining could be considered as one of the mechanisms involved in the formation of AR in this organism. New data are provided that strains with a relatively lower genotype resistance demonstrate a stronger AR. On the other hand the higher genotype resistance of strains did not abrogate their competence to adapt. A relationship between DNA repair capacity estimated on the basis of single dose treatment and the DNA repair capacity estimated on the basis of the AR is obtained.

Stefka G. Chankova, Nadezhda Yurina

Chapter 4. Flavonoid Biosynthesis Genes in Wheat and Wheat-Alien Hybrids: Studies into Gene Regulation in Plants with Complex Genomes

Pigmentation by flavonoid pigments is the oldest trait employed for studies in genetics. In the current chapter, we describe application of the flavonoid biosynthesis (FB) genes as a model in the study of regulatory-target gene relationships in allopolyploid wheat genome (

Triticum aestivum

, AABBDD,

2n = 6x =

42) and gene functioning in a foreign background in wheat-alien hybrids. Investigation of this multicomponent gene system showed that FB gene regulation cuts across genomes of allopolyploid wheat, the regulatory FB genes contribute more to the functional divergence between the diploid genomes of allopolyploid wheat than do the structural genes, and a good cooperation of the wheat and alien FB gene systems is observed in wheat-alien hybrids.

Elena K. Khlestkina, Olesya Tereshchenko, Elena Salina

Chapter 5. Implications for Human and Environmental Health of Low Doses of Radiation

Recent advances in our understanding of the mechanisms underlying the biological effects of low dose effects of ionizing radiation have revealed that similar mechanisms can be induced by chemicals in the environment. Therefore interactions between radiation and chemicals are likely and that the outcomes following mixed exposures to radiation and chemicals may not be predictable for human health, by consideration of single agent effects. Our understanding of the biological effects of low dose exposure has undergone a major paradigm shift. We now possess technologies which can detect very subtle changes in cells due to small exposures to radiation or other pollutants. We also understand much more now about cell communication, systems biology and the need to consider effects of low dose exposure at different hierarchical levels of organization from molecules up to and including ecosystems. We also understand at least in part, some of the mechanisms which drive low dose effects and which perpetuate these not only in the exposed organism but also in its progeny and even its kin. This means that previously held views about safe doses or lack of harmful effects cannot be sustained. ICRP and all national radiation and environmental protection organisations have always accepted a theoretical risk and have applied the precautionary principle and the LNT (linear-non-threshold) model which basically says that there is no safe dose of radiation. Therefore even in the absence of visible effects, exposure of people to radiation is strictly limited. This review will consider the history of the new discoveries and will focus on evidence for emergent effects after mixed exposures to combined stressors which include ionizing radiation. The implications for regulation of low dose exposures to protect human health and environmental security will be discussed.

Carmel E. Mothersill, Colin B. Seymour

Chapter 6. Role of Epigenetic Changes in Radiation-Induced Genome Instability

Ionizing radiation (IR) is an important diagnostic and treatment modality, yet it is also a potent genotoxic agent that causes genome instability and carcinogenesis. While modern cancer radiation therapy has led to increased patient survival rates, the risk of radiation treatment-related complications is becoming a growing problem as radiation poses a threat to the exposed individuals and their progeny. Radiation-induced genome instability, which manifests as an elevated mutation rate (both delayed and non-targeted), chromosomal aberrations and changes in gene expression, has been well-documented in directly exposed cells and organisms. However, it has also been observed in distant, naïve, out-of-field, ‘bystander’ cells and their progeny. Enigmatically, this increased instability is even observed in the pre-conceptually exposed progeny of animals, including humans. The mechanisms by which these distal effects arise remain obscure and, recently, have been proposed to be epigenetic in nature.

Epigenetic alterations which comprise mitotically and meiotically heritable changes in gene expression that are not caused by changes in the primary DNA sequence, are increasingly being recognized for their roles in health and disease. Three major areas of epigenetics—DNA methylation, histone modifications and small RNA-mediated silencing, are known to have profound effects on controlling gene expression. Yet, the exact nature of the epigenetic changes and their precise roles in IR responses and IR-induced genome instability still need to be delineated. Here we will focus on the nature of epigenetic changes in directly exposed and bystander tissues. We will also discuss the emerging evidence that support the role of epigenetic deregulation in transgenerational effects.

Slava Ilnytskyy, Jody Filkowski, Olga Kovalchuk

Chapter 7. Radiation and Terror

This paper is presented to examine certain radiological aspects of terrorism, and to demonstrate that the perception of any event, and the consequent reaction to that perception, is more important than the reality of the event. Radiation, as a terrorist weapon, has been considered for a number of years. A report from 1969 (classified for 15 years) examined radiation sickness or death caused by surreptitious administration of ionizing radiation to an individual [1]. It was initiated because of a suggestion that Alexander Dubcek, Czeckoslovak Communist Party Leader, had radiation sickness due to radiation exposure or consumption of radioisotopes during his August 1968 captivity in Moscow.

Colin B. Seymour, Carmel E. Mothersill

Chapter 8. Bystander Effects and Adaptive Responses Modulate In Vitro and In Vivo Biological Responses to Low Dose Ionizing Radiation

We have utilized cellular and molecular approaches to characterize biological effects that are induced in normal mammalian cells and tissues exposed to low doses/low fluences of ionizing radiations that differ in their quality (i.e. linear energy transfer; LET). In human cells exposed to particulate radiations with high, but not low, LET character, the induced stressful effects were not only confined to the cells that have been directly targeted by the radiation, but involved a number of non-targeted and delayed effects. Chromosomal damage and oxidative changes in proteins and lipids were detected in cells exposed to alpha and high charge and high energy (HZE) particles and in their neighboring bystanders. Signaling events mediated via inflammatory cytokines and/or intercellular channels that comprise gap junctions were critical for the expression of the induced non-targeted effects. With relevance to health risks, the stressful changes in bystander cells were propagated to their progeny. In contrast, induced DNA repair and antioxidant defense mechanisms often attenuated the basal level of DNA damage and oxidative stress to below the spontaneous rate in tissues of animals and in cultured rodent and human cells exposed to low dose/low dose-rate γ rays, a low LET radiation. Together, our data suggest that low dose radiation-induced signaling events act to alter the linearity of the dose-response relation that is predicted by biophysical arguments. They show that the nature of the altered responses strongly depend on radiation quality.

Jie Zhang, Manuela Buonanno, Geraldine Gonon, Min Li, Mariann Galdass, Grace Shim, Sonia M. De Toledo, Edouard I. Azzam

Chapter 9. Inter-plant Communication of Genome Instability in Radiation Exposed Arabidopsis

Bystander effect is the phenomenon of the response of naïve bystanding cells or organisms to the stress experienced by neighboring cells or organisms. It is well documented for animal cells grown in vitro, and there are some reports of similar response on the level of the whole organism and even between stressed and non-stressed organisms. Here we present the evidence of the existence of communication between stressed and non-stressed plants. We show that naïve plants neighboring plants exposed to X-ray or UVC exhibit similar increase in the frequency of homologous recombination as exposed plants. We present the evidence that communication signal is primarily airborne.

Franz Zemp, Igor Kovalchuk

Chapter 10. Direct and Reverse Bystander Effect Between Irradiated and Unirradiated Organisms: The Modulating Role of Chemosignalling in Ecology

It was shown that mice or rats exposed to sublethal dose of ionizing radiation are able to decrease the immune reactivity of intact animals when them kept together in the same cage. Even one individual can cause such a disturbances of immunity in a group of intact animals. The data indicate that at early stage after exposure to sublethal doses of ionizing radiation mice secrete volatile components (VC) in urine which decreased thymus dependent humoral immune response in intact animals (to 60–70% relative control). The stable effect observed as a result of 1-day exposure allowed us to study the time course of secretion of immunosuppressive VC by irradiated animals. These VC possess attractive properties for the intact individuals. The irradiated mice showed an increased attractiveness to intact individuals. The biological significance of a combination of the immunosuppressive and attractive effects of VC is unclear. It is supposed, that mammals possess of the distant immunomodulating chemosignal system, aimed at the immunoreactivity of individuals with immunodeficiency state.

It was established that VC of intact mice restored the humoral immune response and other parameters of immunity in irradiated with a dose of 1 Gy animals. In this case, the irradiated recipients demonstrated an increase of humoral immune response to 140–170%. These VC of intact mice activated at irradiation mice phagocytic activity peritoneal macrophages. Exposure of rats for the third day after irradiation (1 Gy) to the VC of intact animals significantly increased the number of red blood cells, lymphocytes and granulocytes in the bloodstream.

Thus, direct and reverse bystander chemosignaling between the irradiated and intact, irradiated and irradiated animals mediate the modification of immunity and behavioral reactions of recipients. Apparently these untargeted effects of radiation spreading from one individual to another can have a significant impact on the viability of the entire population of animals.

B. P. Surinov, V. G. Isayeva, A. N. Sharetsky

Chapter 11. Molecular-Genetic Analysis of Genetic Predisposition to Myocardial Infarction and Comparison of Risk Factor Population Rates in Different Countries

Factor V Leiden and Protrombin G20210A mutations as well as some gene polymorphisms, such as Val34Leu of the coagulation factor XIII, 4G/5G of PAI-1 gene and Thr312Ala of fibrinogen alpha chain have been investigated as risk factors of myocardial infarction (MI). The methods of polymerase chain reaction (PCR) with specially designed allele specific primers were used to determine polymorphisms and mutations. DNA extracted from lymphocytes or dried bloodspots was used as matrix for PCR. Blood samples of 175 patients with acute myocardial infarction and 270 people of the control group were investigated. It was obtained that the rate of Thr312Ala heterozygotes among patients with myocardial infarction was 1.3 times as high as in the control group. The frequency of Factor V Leiden and G20210 mutations in patients with myocardial infarction was more than 2 times as high as in the control group. Leu/Leu genotype was shown to be responsible for risk of myocardial infarction development too (OR = 2.02). According to our data 4G/4G genotype of the PAI-1 gene may be predisposing to the myocardial infarction and 5G/5G one – protecting. Population frequencies of MI genetic risk factors in Belarus population have been established. The comparison of MI predisposition genotypes frequencies with the levels of this disease in different countries of Europe has been performed. We revealed a statistically significant positive correlation between the frequencies of MI morbidity and 4G/4G genotype. At the same time, there was no statistically significant correlation between frequencies of other risk factors and MI frequency. The obtained data allows conclusion that PAI-1 gene genotype 4G/4G is the most informative for evaluation of genetic predisposition to MI.

Alexander Gonchar, Maxim Ameliyanovich, Kristina Zhur, Irma Mosse, Konstantin Mosse

Chapter 12. Genomic Instability in the Offspring of Irradiated Parents

The review describes the phenomenon of epigenetic transgenerational effects detected in the offspring of irradiated parents. The results of some recent studies showing elevated mutation rates in the non-exposed offspring of irradiated parents are presented and discussed. The possible mechanisms and implications of transgenerational instability are also discussed.

Yuri E. Dubrova

Chapter 13. Low Dose Responses of Bone Marrow to X-Rays In Vivo

Radiation risk at low doses is determined by linear extrapolation from high dose epidemiological data. In the last decade many non-targeted effects have been reported which may be relevant to low dose risk determination. To investigate cell responses at such low doses we used bone marrow cells of mice. We have not observed non-targeted effects long- or short-term post irradiation. Exposure below 50–100 mGy provides no evidence of a dose response for apoptotic signaling, bystander effects and low responses for p53 and p21 induction with significant individual variability. There is also no evidence for long-term chromosomal instability in the bone marrow at doses below 1 Gy. The data also demonstrate unexpected thresholds above which dose-dependent damage signaling is observed and the chromosomal instability phenotype is induced. The data are consistent with low dose X-irradiation being less damaging than would be expected from the LNT paradigm.

Nikolay A. Zyuzikov, Philip J. Coates, Sally A. Lorimore, Eric G. Wright

Chapter 14. Pheromones and Adaptive Bystander-Mutagenesis in Mice

The genomic instability has been studied by cytogenetic analysis of chromosome aberrations in somatic and germ cells of CBA mouse strain. It was shown that volatile substances (VS) excreted by unisex groups of animals into the environment induce genomic instability in conspecifics of same sex depending on the state of VS-donors. Different pretreatments of donor animals modified the cytogenetic effect of their VS in recipients. The meaning of such pheromonal “bystander” effects for animal fitness is discussed.

Eugene V. Daev, Timofey S. Glinin, Anna V. Dukelskaya

Chapter 15. Statistical Model of Adaptation Risk Assessment of Chromosomal Instability

One of the modern problems of radiobiology and radioecology is risk assessment of chromosomal instability in populations that experienced low radiation effects. For these calculations the probability model of adaptation can be used which we suggested earlier (Korogodina VL, Florko BV: Evolution processes in populations of plantain, growing around the radiation sources: changes in plant genotypes resulting from bystander effects and chromosomal instability. In: Mothersill C, Seymour C, Mosse IB (eds.) A challenge for the future. Springer, Dordrecht, pp 155–170, 2007). Purpose: description of adaptation processes in population and risk assessment of genetic instability. Materials: numbers of chromosome abnormalities in cells and cells with abnormalities in rootlets meristem of seeds collected near the radiation sources; frequency of abnormal blood lymphocytes in samples of persons living in the Tyumen and Irkutsk regions of Russia. Methods: statistical modeling. Results and discussion. An adaptation process can be presented as primary and late damaging processes accompanied by selection which is described by Poisson and geometrical laws. Influence of low radiation intensity on chromosomal instability was analyzed; a continued adaptation process in four generations was shown. Risk of chromosomal instability can be determined by means of the P- and G-distributions parameters. Conclusions. Type and structure of model distributions can indicate adaptation processes in population, or its genetic stability. Accumulation of abnormalities and risk of chromosomal instability in resistant subpopulation can be determined by sample mean of P-distribution. Sample mean and value of G-distribution indicate intensity of damaging and selection in sensitive subpopulation.

V. L. Korogodina, B. V. Florko, L. P. Osipova

Chapter 16. Effects of Bystander Factors Induced In Vivo in Blood of People Affected by Chernobyl Accident

The purpose of this work was the analysis of the effects of bystander factors from blood sera of people affected by the Chernobyl accident on human keratinocyte cell culture (HPV-G cells). A new method was developed for evaluation of bystander factor presence

in vivo

in blood of people irradiated by the Chernobyl accident. Affected population groups included liquidators of the Chernobyl accident and people living and working in areas of Gomel region contaminated by radionuclides. The analysis has shown that bystander factors persist in Chernobyl liquidator blood samples for more than 20 years since irradiation. The data suggest that blood sera contain bystander factors, which are able to induce micronuclei and decrease metabolic activity of HPV-G cells.

Pavel M. Marozik, Irma B. Mosse, Sergey B. Melnov, Mikhail S. Marozik, Carmel E. Mothersill, Colin B. Seymour

Chapter 17. Association Study of the Frequencies of Spontaneous and Induced Chromosome Aberrations in Human Lymphocytes

The data on the frequencies of chromosome aberrations in lymphocytes of peripheral blood of 99 volunteers depending on genotypes by genes of xenobiotics detoxification before and after γ-irradiation with the dose of 1 Gy

in vitro

are presented. The frequencies of aberrations were estimated by analyzing not less than 500–1,000 metaphases per person. The data of the cytogenetic analysis were compared with the results of PCR genotyping by the genes of xenobiotics detoxication (

CYP1A1, CYP2D6, GSTM1

,

GSTT1, GSTP1

,

COMT, NAT2

), genes of DNA repair (

XRCC1, XPD

,

ERCC1, APEX1

,

RAD23B, OGG1

,

ATM

) as well as by the genes of oxidative response and cell cycle regulation (

SOD2, CAT

,

GCLC, MTHFR, Tp53

). The frequency of spontaneous aberrations of chromosome type was reduced for homozygotes by the deletion of

GSTM1

locus, especially for double homozygotes by the deletions of

GSTM-GSTT1

genes. The mentioned frequency increased additively with the number of copies of the minor allele variants

XPD*

2251 G and

XPD*

862A of gene of excision repair

XPD

(

p

= 0.025). The frequency of γ-induced chromosome aberrations proved to be elevated for the carriers of a minor allele

OGG1*

977 G (

p

= 0.011). The significantly elevated number of γ-induced chromosome aberrations was also observed for the carriers of major alleles

XRCC1*

G1996 and

XRCC1*

C580 (

p

= 0.002). The frequency of γ-induced chromosome aberrations proved to be reduced for G/G homozygotes by a minor allele of poorly studied site

CYPA1

T606G: 0.094 ± 0.006 against 0.112 ± 0.002 for the carriers of allele T (

p

= 0.004). The results of meta-analysis of the data of 14 works on the effect of genotype by

GSTM1

locus on the frequency of cytogenetic anomalies in the control and exposed populations are discussed.

Luybov Sal’nikova, Anastasia Chumachenko, Alexander V. Rubanovich

Chapter 18. Radioecology of the Future: The Problem of Final Geological Disposal of Radioactive Wastes

The ethical principle according which the concept of “sustainable development” implies “

satisfying the needs of the present, without compromising the ability of future generations to meet their own needs

” is considered to be and absolute principle. Nevertheless also absolute principles have a their own range of application. Outside such a range they may lead to unwanted situations. With reference to radioactive wastes they should be managed in a way that secures an acceptable level of protection for human health and the environment, and affords to future generations at least the level of safety, which is acceptable today, But by referring to the rate of evolution of the human society with an extremely great increase in the last centuries, it is not possible to consider the far future generations as equivalent to the current one. In particular, the trend of evolution of the human society forecasts a strong acceleration never observed till now. Consequently the habits of the far future generations will be totally different from the today. Therefore also the criteria to be adopted for the safe containment of a geological repository must be take into account this fact. In fact it must be stressed that an excessive degree of protection implies, very often, only a waste of resources without any advantage and implying an absolute negative balance.

Arrigo A. Cigna

Chapter 19. Reproductive Effects from Chronic, Multigenerational, Low Dose Rate Exposures to Radiation

Relatively few experiments have been conducted on the effects to organisms following long-term exposures to low levels of radiation. Even fewer studies have examined the effects of radiological exposures to multiple generations of organisms. Speculations that damage will accumulate and be greater with each passing generation are plausible. Alternative, opposing views that adaptive response and repair mechanisms will counter the effects, such that damage does not increase with each generation, are equally plausible. Few data exist to support one hypothesis over the other, particularly for chronic, low-level exposures to vertebrate organisms. Our research explored exposures of low-dose irradiation to multiple generations of a model vertebrate organism, Japanese medaka (

Oryzias latipes

), one of the most widely used fish in comparative mutagenesis and carcinogenesis studies. A unique outdoor irradiation facility allowed us to examine effects to five generations of medaka that were continuously irradiated to different dose rates. The dose rates bracketed the IAEA guideline for acceptable chronic exposures to aquatic wildlife (10 mGy day

−1

), and thus were a test to see if the guidelines were applicable for multigenerational exposures. The effects on reproductive endpoints that might influence population dynamics were examined. Our intention was to test the hypothesis that multigenerational exposures to low dose rate irradiation are no more damaging, as measured by reproductive characteristics that could potentially impact a population, than damage incurred from exposure to a single generation. The data suggest that total accumulated dose may be more meaningful than dose rate when trying to predict effects to populations of chronically exposed organisms. Such knowledge is needed because chronic exposure to low levels of radiation is a more likely scenario for nuclear workers, and to wildlife exposed to routine releases from nuclear facilities.

Thomas G. Hinton, Daniel Coughlin, Yi Yi, Travis Glenn, John Zimbrick

Chapter 20. Aquatic Biota within the Chernobyl Accident Exclusion Zone: Consequences of the Long-Term Radiation Exposure

The effects of chronic radiation exposure on aquatic biota within the Chernobyl accident exclusion zone during 1998–2009 were studied. The absorbed dose rate for hydrobionts registered in range from 1.3 mGy/year to 3.4 Gy/year. The heightened chromosomal aberration rate in the embryo tissue of snails (up to 27%) and in the root meristems of higher aquatic plants (up to 18%) was determined. In hemolymph of snails from contaminated lakes the quantity of death cells averages 36–44%; the part of phagocytic cells averages 41–45%, as well as decrease of the young amoebocytes quantity to 10–20%. In peripheral blood of fish the high rate of abnormal red cells (up to 29‰) as different type of invaginations, ramifications, micronuclei etc. was marked. The high level of parasitic fungi and gall-producing arthropods of the common reed in the most contaminated lakes within the exclusion zone was registered. Above mentioned phenomenon may testify upon the decreasing of the parasitical stability of plant under impact of long-term radiation exposure.

Dmitri Gudkov, Elena Dzyubenko, Natalia Shevtsova, Natalia Pomortseva, Sergey Kireev, Alexander Nazarov

Chapter 21. Endless Pursuit of DNA Double-Strand Break Ends

In the pursuit of radiation-induced cellular damage that manifests in cell killing and genome instability, but is reversible by the phenomenon of liquid holding, DNA double-strand breaks (DSBs) have been shown to be the major culprit. It is now widely accepted that DSBs provide both beneficial and deleterious effects and that elaborate systems were evolved to address their detection, processing and repair. Understanding the mechanisms of DSB induction, processing and eventual biological consequences as well as just the detection of DSBs remain a challenge – especially for randomly induced breaks. Given the large number of extensive reviews available and the limited space here, I have chosen to focus on summarizing recent novel findings from our group using the budding yeast

Saccharomyces cerevisiae

that are relevant to many molecular and genetic aspects of DSB repair and impact on genome stability. Included are the systems we have developed that address (1) induction of random primary and secondary DSBs; (2) processing of DSB ends; (3) genetic control of DSB induction and repair; (4) genome instabilities associated with DSBs including rearrangements and hypermutability associated with resected ends; and (5) physical factors that determine the transition from DSB to chromosome break or recombination. Using a circular chromosome, we find that resection of random, dirty-end DSBs induced by ionizing radiation or derived from MMS single-strand damage is rapid and is primarily due to the MRX complex. Interestingly, the transition from DSB to chromosome break at a unique DSB in yeast is largely prevented by the nuclease function of exonuclease 1 as determined from separation of fluorescent markers that flank a DSB. Based on a tetraploid gene-dosage model, the role of the chromosome structural complex cohesin is not only to enhance DSB repair between sister chromatids, but it also directs recombinational repair events to sisters thereby preventing loss of heterozygosity. Notably, DSBs greatly sensitizes cells to localized mutability as well as gross rearrangements. Overall, these findings demonstrate the genomic vulnerability to DSBs and the genetic investment in their orderly processing.

Michael A. Resnick

Chapter 22. Facultativeness Principle and Generalized Approach to the Genome and Hereditary Variability

Facultativeness in the genome structure and function reflects the general principle of the life organization and evolution:

the unity of the whole and the freedom of the parts.

The genome or cell hereditary system codes, maintains and transfers the hereditary information in both structurally and dynamically. Generalized genome concept presents a genome as an ensemble of both obligate and facultative elements. Template processes (Replication, Transcription and Translation) and Basic genetic processes (Repair, Recombination and Segregation) are capable of functional facultativeness and dynamic (epigenetic) alterations. It is reasonable to discriminate between three kinds of heritable changes – mutations, variations and epigenetic alterations. Structural genome facultativeness is expressed as a subdivision of cell DNA and RNA elements on two subsystems: Obligate genetic elements (OGE) and Facultative genetic elements (FGE). FGE include various kinds of repeated sequences, mobile elements, amplicons, inserted viral and foreign DNA, B-chromosomes, plasmids and cytobionts. The number and intracell topography of FGE varies from cell to cell, in different tissues and individuals. Changes in structure or order of OGE are mostly correspond to classical mutations. For diverse changes in number or cell/tissue topography of FGE (as it is well known for mobile elements) the term

variations

seems appropriate. Mutations and variations significantly differ on the character and mode of their occurrence. Variations may occur simultaneously in many cells/individuals and are induced by non-mutagenic factors. Spontaneous hereditary changes in nature usually occur in the system ENVIRONMENT – FGE – OGE via two-step mechanism. FGE are the first to react to both internal and external environmental challenges. Then their activation induces gene/chromosomal mutations. Both variations and epigenetic alterations (epimutations) may have non-mendelian features, occur simultaneously in many individuals, sometimes reminding phenomenon of inheritance of acquired characteristics.

Michael Golubovsky

Chapter 23. Recent Inserts of Transposable Elements Affect Structure and Functions of Human Genome

Transposable elements (TEs) are selfish fragments of DNA able to reproduce themselves into the host genomes. TEs typically occupy ∼40–50% of the mammalian genomes. In our studies, we focus on evolutionary recent TE inserts that appeared in the DNA of human ancestor lineage after divergence with the chimpanzee ancestry,

i.e.

less than ∼6 million years ago. These human specific elements (hsTEs) represent only a minor fraction of the whole TE cargo of the human genome. hsTEs are represented by the four families called HERV-K(HML-2), L1, Alu and SVA. The number of human specific copies for HERV-K(HML-2), L1, Alu and SVA families is approx. 150, 1,200, 5,500 and 860 copies per genome, respectively. Taken together, hsTEs shape ∼6.4 megabases of human DNA, which is about 6-times lower than what is occupied by the human specific simple nucleotide polymorphisms, and 23-times smaller than the overall length of human specific deletions and duplications. However, although modest in terms of genomic proportion, hsTEs should be regarded as the perspective candidates for being molecular genetic agents of human speciation. Unlike most of random mutations and duplications, each novel insert of hsTE has provided to the recipient genomic locus a set of functional transcriptional factor binding sites positively selected during the TE evolution. For example, clusters of novel inserts of Alu elements may serve as CpG islets, SVA elements provide functional splice sites and polyadenylation signals, whereas L1 and HERV-K(HML-2) elements donate enhancers, promoters, splice sites and polyadenylation signals. Significant proportion of the human-specific genomic deletions, duplications and translocations has been also generated due to ectopic recombinations between the different individual TE inserts. Among the other, we report for the first time a detailed functional characteristics of the HERV-K(HML-2) hsTEs done at the genome-wide level. We have identified 65 active

in vivo

human specific promoters contributed by these elements. We also identified three cases of the hsTE-mediated human specific transcriptional regulation of functional protein-coding genes taking part in brain development during embryogenesis. We found ∼180 human specific polyadenylation signals transferred by the SVA elements into the introns of known functional genes. Scaling of these data to the total number of the hsTEs predicts that hundreds of human genes are regulated by these elements. Finally, we discovered the first exclusively human specific TE family, represented by ∼80 members formed by a combination of a part of a CpG islet of human gene

MAST2

ansd of the 3′-terminal part of an SVA retrotransposon. According to our estimates, this family, termed CpG-SVA, was far more active than the ancestral SVA family. Our data indicate that

MAST2

regulatory sequence was recruited during the evolution to provide effective CpG-SVA transcription in human testicular germ-line cells.

Anton Buzdin, Maria Suntsova, Olga Bantysh, Elena Aleksandrova, Anastasia Zabolotneva, Elena Gogvadze, Nurshat Gaifullin

Chapter 24. Ecological Risk Assessment to Benthic Biocenoses

On the basis of experimental data and cytogenetic studies of marine and freshwater invertebrates natural populations it was shown that different species had approximately equal part (%) of full value posterity at the same average level of chromosome mutagenesis for populations, independing on deleterious factors and females fecundity. This phenomenon made it possible to calculate specimens reproductive contribution for species with different females fecundity and to assess expected reduction of population adaptive potential and the increase of ecological risk at different levels of population damage. It is suggested that the adaptation to pollution will be more effective in populations with high female fecundity. Adaptive possibilities of populations and the resistance of posterity were considered as a alternative properties of populations Ranges of chromosome mutagenesis critical levels for different hydrobionts taxons were determined. An algorithm of ecological risk assessment to benthic communities was proposed.

V. G. Tsytsugina

Chapter 25. Molecular Changes in Radiation Induced Thyroid Carcinomas in Mice

Thyroid carcinomas arising from follicular epithelial cells are the most common endocrine malignancy in man. During studies performed on the population of the Marshall-Islands and after the accident at the Chernobyl nuclear power plant in 1986 a large increase in benign thyroid nodules and thyroid cancer, especially among children was shown. Thyroid follicular carcinomas are categorised into 3 histotypes: papillary, follicular, and undifferentiated (anaplastic). Papillary thyroid carcinomas are the predominant type of the thyroid cancer in patients exposed to external radiation, particularly in children. The classic oncogenic genetic alterations commonly seen in thyroid cancer include RET/PTC rearrangements, Ras point-mutations, PAX8-peroxisome proliferator-activated receptor γ (PPARg) fusion oncogene and BRAF mutation. For some families that share the FNMTC syndrome (familiar follicular nonmedullary thyroid carcinoma) a predisposition to thyroid tumors has been described. The genes responsible for FNMTC have been identified through linkage analyses of the affected families, TCO (thyroid tumors with cell oxyphilia), PRN1, and NHTC1. This study investigates gene changes in radiation induced follicular thyroid carcinoma. Following low dose exposure of the thyroid by off-targeted irradiation of the alpha-emitter

227

Thorium, 5 cases of Follicular thyroid carcinomas (FTC) and 1 case of thyroid hyperplasia developed in a highly susceptible mouse strain. In such cases, Comparative Genomic Hybridization (CGH) for numerical changes was performed on the whole genome. Copy number loss affecting the entire chromosome 14 in 3 out of 6 cases was observed. A similar pattern of chromosome 14 deletions was already reported in thyroid tumours of other mouse strains following high-dose exposure or oncogene activation and therefore suggests that this deletion is not associated with genetic predisposition in different mouse strains to thyroid tumourigenesis.

O. Klymenko, K.-J. Heiliger, I. Gonzalez Vasconcellos, C. Dalke, M. J. Atkinson, M. Rosemann

Chapter 26. Study of Arabidopsis thaliana Patterns of Experimental Mutational Variability

A summary of results of prolonged genetic and physiological research initiated by N.V. Timofeev-Ressovsky and carried out based on the unique genetic collection of the mutants of the classical model object –

Arabidopsis thaliana

– under the leadership and immediate participation of P.D. Usmanov in the Laboratory of Physiological Genetics of the Genetic Department of the Institute of Plant Physiology and Genetics of the Academy of Sciences of the Republic of Tajikistan.

The article contains the following: the summary of development of the Arabidopsis genetic collection; the results of the study of the Arabidopsis mutation variability; creation of the wide spectrum of mutant forms differing by their phenotype, the study of their genetic nature and physiological and biochemical peculiarities; the analysis of the genotypic variability of the photosynthetic apparatus characteristics in order to ascertain the mechanism of the photosynthesis genetic control and interrelations between the cell organelle (karyon, chloroplasts, mitochondrion).

Based on the complex genetic, physiological and biochemical study of the mutant lines from the mentioned Arabidopsis collection, there have been established experimental model systems for ecological and genetic research, and the systems for evaluation of the impact of extreme factors and anthropogenic influence on the gene pool of plant populations and analysis of genetic mechanisms of plants adaptation.

Olga Usmanova, Timur Usmanov

Chapter 27. Methods for Predicting 137Cs Contamination Levels of Soil Suitable to Obtain Plant and Fodder Products in Compliance with the Adopted Standards

Using southern districts in the Kaluga region affected by the Chernobyl accident as an example, a comparative analysis has been made of estimated levels of

137

Cs contamination of agricultural lands with data of real measurements. The estimated data which consider only the radionuclide decay are quite reliable, however for better accuracy scales of agrotechnical countermeasures need to be considered.

Alexey V. Panov, Rudolf M. Alexakhin, Anna A. Muzalevskaya

Chapter 28. Effects of Chronic Irradiation in Plant Populations

An assessment of the state of plant and animal populations inhabiting polluted territories and the analysis of mechanisms of their adaptation to adverse environmental conditions undoubtedly have general biological importance. Consequently, studies that examine biological effects on non-human biota in natural settings provide a unique opportunity for obtaining information about the potential biological hazard associated with radioactive contamination. The results of long-term field studies in the Bryansk region of Russia affected by the Chernobyl accident and in the Semipalatinsk Test Site, Kazakhstan are presented. Although radionuclides cause primary damage at the molecular level, there are emergent effects at the level of populations, non-predictable solely from knowledge of elementary mechanisms of the pollutants’ influence. Plant populations growing in areas with relatively low levels of pollution are characterized by the increased level of both cytogenetic disturbances and genetic diversity. Radioactive contamination of the plant environment activates biological mechanisms, changing a population’s resistance to exposure. However, there are radioecological situations where enhanced radioresistance has not evolved or has not persisted.

Stanislav Geras’kin, Alla Oudalova, Nina Dikareva, Elena Chernonog, Julia Prytkova, Vladimir Dikarev, Tatiana Novikova

Chapter 29. Reduced Rb1 Expression Causes Impaired Genome Stability in Bone-Cells and Predispose for Radiation-Induced Osteosarcoma

The risk of cancer after exposure to ionizing radiation is currently defined only as a function of the received dose. Genetic factors that modify individual susceptibility to radiation-induced cancer are excluded from the risk assessment. We report the mapping of QTLs that confer increased susceptibility to radiation-induced osteosarcoma in the mouse. The strongest candidate locus, on chromosome 14, contains a functional polymorphism weakening the efficiency of the Rb1 promoter. The Rb1 allele associated with increased susceptibility is preferentially retained during allelic loss at the Rb1 gene in radiation-induced tumors. In combination with allelic losses of CDKN2a/P16, an upstream regulator of Rb1, 100% of all analyzed tumors exhibit a defect affecting this pathway. Alpha-irradiation of knockout mice with a bone-specific expression reduction of Rb1 or P16 confirmes that these genes can alter the susceptibility for osteosarcoma, either by increasing the tumor-risk or by shortening their latency. These results suggest that common germ-line polymorphisms causing impaired expression of known tumor-suppressor genes can modify individual susceptibility to radiation-induced cancer.

Michael Rosemann, Iria González-Vasconcellos, Tanja Domke, Michaela Nathrath, Mike J. Atkinson

Chapter 30. Biophysics of Heavy Ions

Densely ionizing radiation, such as heavy ions, produce biological damage which is different from that normally produced by sparsely ionizing radiation, such as X- or γ-rays which are a large component of the natural radiation background. In fact, as a result of the different spatial distribution of the energy deposited, along the core and penumbra of the track, DNA lesions are exquisitely complex, and difficult to repair. RBE factors are normally used to scale from X-ray to heavy ion damage, but it should be kept in mind that RBE depends on several factors (dose, dose rate, endpoint, particle energy and charge, etc.) and sometimes heavy ions produce special damages that just cannot be scaled from X-ray damage. The special characteristics of heavy ions can be used to treat tumors efficiently, as it is currently done in Japan and Germany.

Marco Durante

Chapter 31. De Novo Mutations in Y-Chromosome STR Loci Revealed in Paternal Lineages of Siberian Tundra Nentsi Population

Y-chromosome short tandem repeats (STR) markers are widely used in human population genetic studies and forensic applications. Estimation of Y-STR mutation rate has a key role for dating the origin of Y chromosome lineages and for paternity tests. Previous studies demonstrated significant interlocus difference in mutation rate and the positive correlation to STR repeat length. The different ethnic groups and various Y-chromosome haplogroups defined by single-nucleotide polymorphisms were characterized by different Y-STR mutation rates. To date no Y-STR pedigree mutation studies were reported in native Siberian populations. Siberian Tundra Nentsi population possesses many unique genetic features and represents a good model for genealogical studies because of large family sizes, available ancestry information and relatively isolated life style in the extreme north environment. We thoroughly selected 50 paternal lineages with deep genealogical depth from 2 to 6 generations with the total number of 330 males. The number of descendants varied from 2 to 25 per paternal lineage, in average seven males per lineage. We also included in our analysis six Komi, three Russian and one Khant families who lived in the same villages. Totally 34 STR loci from non-recombining part of Y-chromosome were studied: DYS19, DYS390, DYS391, DYS393, DYS385A, DYS385B, DYS426, DYS388, DYS392, DYS439, DYS389-1, DYS389-2, DYS458, DYS447, DYS449, DYS459, DYS454, DYS464, DYS455, DYS457, DYS448, H4, DYS607, CDY-1, CDY-2, DYS460, YCA-1, YCA-2, DYS576, DYS570, DYS438, DYS456, DYS442, and C4. Eleven males (4%) had different alleles in six or seven STR loci compared to their paternal ancestors. We believe that those men were born out-of-wedlock or were adopted. Traditionally native Siberian people adopt and raise all children who lost their parents. Mutations were observed in 21 out of 34 Y-STR loci. We found relatively higher number of mutation gains (60%) versus losses. Our study has thus shown that the chosen Y-STR loci represent a powerful tool to estimate mutation rates for forensic and population genetic purposes.

Ludmila Osipova, Tatiana Karafet, Michael Hammer

Chapter 32. Effects of Chronic Gamma Irradiation on Reproduction in the Earthworm Eisenia fetida

In recent years ecological impacts of ionizing radiation have emerged as an important research field. But there are still considerable knowledge-gaps regarding biological effects of chronic irradiation in wildlife, particularly for endpoints related to reproduction. Reproduction is considered to be one of the most sensitive radiation-associated endpoints, and determines not only the fate of the single organism, but may also influence population dynamics and the balance of higher ecological units. Based on their radioecological properties and their important role in the soil ecosystem, earthworms have been identified by ICRP as one of the reference animals and plants (RAPs) to be used in environmental radiation protection. This paper will present results of a series of studies carried out on the effects of ionising radiation on earthworms, covering long term-effects on reproduction, as well as studies on biological processes such as recovery, acclimatization and adaptive response, using a number of molecular biomarkers. The aim is to show how the studies can improve predictions of the way individuals and populations respond to chronic exposures of ionising radiation.

Deborah H. Oughton, Turid Hertel-Aas, Alicja Jaworska, Gunnar Brunborg
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