Genome Stability: From Virus to Human Application

Genome Stability

From Virus to Human Application

Editors

Igor Kovalchuk

Olga Kovalchuk

University of Lethbridge, Lethbridge, AB, Canada

Table of Contents

Cover image

Title page

Translational Epigenetics Series

Copyright

List of Contributors

Introduction

Chapter 1. Genome Stability: An Evolutionary Perspective

1. Introduction

2. Evolution Theories and My Reflection on Them

3. The Role of Symbiosis in Genome Evolution

4. Fixation of a Mutant Allele in a Population

5. Evolution of Mutation Rates

6. Genome Instability: Is It Random?

7. Genome Evolution May Start From Changes at the Level of DNA Methylation or Chromatin Modification

8. Conclusion

Glossary

List of Abbreviations

Section I. Genome Instability of Viruses

Chapter 2. Genetic Instability of RNA Viruses

1. Introduction

2. Overview of RNA Virus Multiplication

3. Viruses as Quasispecies

4. Overview of RNA Virus Replication Mechanisms

5. The Viral Polymerase as a Source of Error

6. Other Viral Determinants of Mutation Rate

7. Recombination

8. The Effect of Replication Mode on Mutation Frequency

9. The Effect of Cellular Factors on Virus Mutation Rate

10. Mechanisms Underlying Genetic Robustness in RNA Viruses

11. RNA Viruses on the Edge

12. Virus Genetic Variability and the Virus–Host Arms Race

13. Taking Advantage of the Mutability of RNA Viruses

14. Conclusion

Glossary

List of Abbreviations

Chapter 3. Genome Instability in DNA Viruses

1. Overview

2. Rates of Spontaneous Mutation and Genetic Diversity of DNA Viruses

3. Mutator Phenotypes Produced by Low-Fidelity DNA Virus Polymerases

4. DNA Coliphages and the MMR System

5. The Interaction Between DNA Viruses and the Eukaryotic DNA Damage Response

6. Diversity-Generating Retro-Elements in Bacteriophages

7. Recombination-Driven Genome Instability in DNA Viruses

8. APOBEC3 Proteins and DNA Virus Genome Instability

9. Conclusions and Future Directions

Glossary

List of Acronyms and Abbreviations

Section II. Genome Instability in Bacteria and Archaea

Chapter 4. Genome Instability in Bacteria and Archaea: Strategies for Maintaining Genome Stability

1. Introduction

2. Reponses to DNA Damage

3. DNA Repair Pathways

4. Restriction-Modification Systems: Protecting the Genome From Invaders

5. Conclusion

Glossary

List of Abbreviations

Chapter 5. Genome Instability in Bacteria: Causes and Consequences

1. Introduction

2. Effects of Stress Responses on Genome Instability

3. Genome Instability Due to Stable Mutator Genotypes

4. Genome Instability Due to Homologous and Illegitimate Recombination

5. Genome Instability Due to Specialized Genetic Elements

6. Genome Instability Due to Genetic Exchange

7. Conclusion

Glossary

List of Abbreviations

Chapter 6. CRISPR: Bacteria Immune System

1. Introduction

2. History of the CRISPR/Cas Discovery

3. Structure of the CRISPR Loci

4. CRISPR/Cas Classification

5. Composition of the CRISPR/Cas Systems

6. Molecular Machines of CRISPR/Cas Systems

7. CRISPR/Cas Systems at Work

8. Other Roles of the CRISPR/Cas Systems

9. Conclusion

Glossary

List of Acronyms and Abbreviations

Section III. Genome Stability of Unicellular Eukaryotes

Chapter 7. From Micronucleus to Macronucleus: Programmed DNA Rearrangement Processes in Ciliates Are Regulated Epigenetically by Small and Long Noncoding RNA Molecules

1. Introduction

2. The Sexual Life Circle of Ciliates

3. Organization of the Micro- and Macronuclear Genomes

4. Epigenetic Regulation of Macronuclear Development in Tetrahymena

5. Epigenetic Regulation of Macronuclear Development in Stichotrichous Ciliates

6. Conclusion

Glossary

List of Abbreviations

Chapter 8. Homologous Recombination and Nonhomologous End-Joining Repair in Yeast

1. Introduction

2. Homologous Recombination Models

3. Common Homologous Recombination Steps

4. Nonhomologous End-Joining

5. Cell Cycle Regulation of Homologous Recombination and Nonhomologous End-Joining

6. Conclusion

Glossary

List of Acronyms and Abbreviations

Section IV. Genome Stability in Multicellular Eukaryotes

Chapter 9. Meiotic and Mitotic Recombination: First in Flies

1. Introduction

2. Mitotic Recombination

3. Meiotic Recombination

4. Drosophila: The Next 100 Years

Glossary

List of Acronyms and Abbreviations

Chapter 10. Genome Stability in Drosophila: Mismatch Repair and Genome Stability

1. Introduction

2. MMR Activity in Drosophila

3. MMR Genes in Drosophila

4. MMR and Microsatellite Instability

5. The Role of MMR in Meiotic Recombination

6. MMR and Somatic Cell Mutation

7. Conclusion

Glossary

List of Abbreviations

Chapter 11. Genome Stability in Caenorhabditis elegans

1. Introduction

2. The Caenorhabditis elegans Model

3. Powerful Genetic Tools to Explore DDR Dynamics

4. Genotoxic Agents for DNA Damage Induction

5. Methods for DNA Damage Detection

6. Excision Repair

7. Mismatch Repair

8. Double-Strand Break Repair in C. elegans

9. DNA-Damage Checkpoints

10. Concluding Remarks

Glossary

List of Abbreviations

Chapter 12. Genetic Engineering of Plants Using Zn Fingers, TALENs, and CRISPRs

1. Introduction

2. Zinc Finger Nucleases for Genome Engineering of Plants

3. TALENs for the Genome Engineering of Plants

4. The CRISPR/Cas9 System for the Genome Engineering of Plants

5. Future Perspectives of the Genome-Editing Technology

Glossary

List of Acronyms and Abbreviations

Chapter 13. Plant Genome Stability: General Mechanisms

1. Introduction

2. DNA-Damaging Agents

3. Sensing DNA Damage

4. Chromatin Architecture and DNA Repair

5. Photoreactivation

6. Base Excision Repair

7. Nucleotide Excision Repair

8. Mismatch Repair

9. DNA Double-Strand Break Repair

10. DNA Repair in Organelles

11. Future Perspective

Glossary

List of Acronyms and Abbreviations

Section V. Genome Stability in Mammals

Chapter 14. Cell-Cycle Control and DNA-Damage Signaling in Mammals

1. Introduction

2. Cell-Cycle Progression in Mammalian Cells

3. DNA-Damage Signaling and Repair in Mammals

4. Checkpoint Control: DNA-Damage Signaling and the Mammalian Cell Cycle

5. Conclusion

Glossary

List of Acronyms and Abbreviations

Chapter 15. The Role of p53/p21/p16 in DNA-Damage Signaling and DNA Repair

1. Introduction

2. The p53 Tumor-Suppressor Protein

3. The p21 Tumor-Suppressor Protein

4. The p16INK4A Tumor-Suppressor Protein

5. Conclusion

Glossary

List of Acronyms and Abbreviations

Chapter 16. Roles of RAD18 in DNA Replication and Postreplication Repair

1. Introduction: The DDR, DNA Damage–Tolerance and DNA Damage–Avoidance Mechanisms

2. Identification of RAD18–RAD6 as a Mediator of DNA Damage Tolerance

3. RAD18-Mediated PCNA Monoubiquitination and the TLS Polymerase Switch

4. RAD18 Structure, Activation, and Coordination With the DDR

5. DNA Replication–Independent RAD18 Activation and TLS

6. RAD18 Functions in Error-Free PRR via Template Switching

7. TLS- and TS-Independent Roles of RAD18 in Genome Maintenance

8. Physiological Roles of RAD18

9. Conclusions and Perspectives

Glossary

List of Abbreviations

Chapter 17. Base Excision Repair and Nucleotide Excision Repair

1. General Overview and Historical Perspectives of Two DNA Excision-Repair Pathways, BER and NER

2. Mammalian BER

3. Mammalian NER

4. Biological Implications Beyond DNA Damage and Repair

5. Interplay Between NER and BER: The Key Role of the DNA-Damage Response for Prevention of Cellular Degeneration

6. Concluding Remarks

Glossary

List of Abbreviations

Chapter 18. DNA Mismatch Repair in Mammals

1. Introduction and Brief History

2. Post-replication Mismatch Repair

3. Mismatch Repair and the DNA-Damage Response

4. Regulation of MMR

5. Future Directions

Glossary

List of Abbreviations

Chapter 19. Repair of Double-Strand Breaks by Nonhomologous End Joining: Its Components and Their Function

1. Introduction

2. Classical NHEJ

3. Alternative NHEJ

4. End Processing

5. Conclusions

Glossary

List of Abbreviations

Chapter 20. Double-Strand Break Repair: Homologous Recombination in Mammalian Cells

1. Introduction

2. The Role of HR in the Equilibrium of Genetic Stability Versus Diversity

3. Molecular Mechanisms and Regulation of HR

4. Roles of HR in Replication Fork Reactivation and DSB Repair

5. The Dark Side of HR: Promotion of Genome Instability

6. Protection Against Excessive HR

7. Homologous Recombination, Genome Stability, and Cancer

8. HR in Genomic Molecular Evolution

9. Concluding Remarks

Glossary

List of Abbreviations

Chapter 21. Telomere Maintenance and Genome Stability

1. Introduction

2. Telomere Length and Telomerase Regulation

3. Organization and Function of TERT and TR

4. Telomeric DNA Structure

5. Telomere-Interacting Proteins

6. Telomere–Telomerase Interactions and Regulation

7. Telomere-Associated Diseases

8. Telomeres As a DNA Damage–Prevention System

9. Conclusions and Closing Remarks

Glossary

List of Acronyms

Chapter 22. The Relationship Between Checkpoint Adaptation and Mitotic Catastrophe in Genomic Changes in Cancer Cells

1. Cancer and Its Hallmarks

2. The Cell Cycle

3. Cell-Cycle Checkpoints

4. Genotoxic Agents as Anticancer Drugs

5. Cell Death

6. Mitotic Catastrophe

7. Dual Modes of Cell Death by the Same Genotoxic Agent

8. The Relationship Between Entry Into Mitosis With Damaged DNA and Genomic Instability

9. A History of Checkpoint Adaptation

10. Checkpoint Adaptation in Human Cells

11. The Consequences of Checkpoint Adaptation

12. The Relationship Between Checkpoint Adaptation and Genomic Instability

Glossary

List of Abbreviations

Chapter 23. Chromatin, Nuclear Organization, and Genome Stability in Mammals

1. Introduction

2. Histones

3. Nucleosomes and the 30-nm Fiber

4. Higher-Order Structures

5. Chromatin Remodelers

6. Access, Repair, Restore

7. Nuclear Organization of Chromatin

8. Chromosome Territories

9. Transcription and Replication in the Nucleus

10. Conclusions

Glossary

List of Abbreviations

Chapter 24. Role of DNA Methylation in Genome Stability

1. Introduction to the Cellular Functions of DNA Methylation

2. Multifaceted Regulation of Genome Stability by DNA Methylation

3. Conclusions and Future Direction

Glossary

List of Acronyms and Abbreviations

Chapter 25. Noncoding RNAs in Genome Integrity

1. Introduction

2. Targeting Bacteriophage Genomes by CRISPR/Cas9

3. DNA Elimination in Ciliates

4. Telomerase RNA and Telomere Length

5. Role of Micro-RNAs in the Regulation of DNA Repair and Genome Stability

6. The Role of Piwi-Interacting RNA in the Maintenance of Genome Stability in the Germline

7. The Role of Small Interfering RNAs in the Maintenance of Genome Stability

8. Conclusion

Glossary

List of Abbreviations

Section VI. Human Diseases Associated With Genome Instability

Chapter 26. Human Diseases Associated With Genome Instability

1. Introduction

2. Rare Genetic Diseases Associated With DNA Repair

3. Cancer and Genome Instability

4. Epigenetic Regulation of Cell Cycle and DNA Repair in Cancer

Glossary

List of Acronyms and Abbreviations

Chapter 27. Cancer and Genomic Instability

1. Introduction

2. DNA-Repair Pathways

3. Genomic Instability in Hereditary Cancer

4. Genomic Instability in Sporadic Cancers

5. Triggering Excessive Genomic Instability by Targeting DNA-Repair Pathways as a Strategy for Cancer Therapy

6. Conclusion

Glossary

List of Abbreviations

Chapter 28. Chromatin Modifications in DNA Repair and Cancer

1. Introduction

2. Interrelationship of DNA and Chromatin

3. Histone Modifications and Chromatin Remodelers

4. Chromatin Modifiers in Genome Stability

5. Replication Stress, Activation of the S-Phase Checkpoint and DNA-Damage Tolerance

6. Overview: The Relationship Between Chromatin and Repair Choice

Glossary

List of Abbreviations

Chapter 29. Genomic Instability and Aging: Causes and Consequences

1. Introduction

2. Age-Related Accumulation of DNA Damage and Genomic Instability

3. Causes of Age-Dependent Accumulation of Genomic Instability

4. Genomic Regions With Various Susceptibility to Genomic Instability

5. Role of Genomic Instability in Aging?

6. Conclusion

Glossary

List of Abbreviations

Chapter 30. Nucleolar Contributions to DNA-Damage Response and Genomic (In)Stability in the Nervous System

1. Introduction

2. Nucleolus As a Sensor of Neuronal DNA Damage

3. Neurodegeneration-Associated Instability of rDNA

4. Concluding Remarks

Glossary

List of Abbreviations

Section VII. Effect of Environment on Genome Stability

Chapter 31. Diet and Nutrition

1. Introduction

2. Dietary Causes of Genomic Instability

3. Dietary Protection Against Genomic Instability

4. The Significance of Genetic Polymorphisms

5. Conclusions

Glossary

List of Abbreviations

Chapter 32. Chemical Carcinogens and Their Effect on Genome and Epigenome Stability

1. Introduction

2. Epigenetic Regulators

3. Effects of Metals

4. Tamoxifen Effects

5. Effects of 1,3-Butadiene

6. Influence of Polycyclic Aromatic Hydrocarbons

7. Conclusions

Glossary

List of Abbreviations

Chapter 33. Environmental Sources of Ionizing Radiation and Their Health Consequences

1. Introduction

2. The Molecular Effects of IR in Cells

3. Radiation Dosage and Linear Energy Transfer

4. Nuclear Military Attacks and Civilian Nuclear Disasters

5. Aerospace Travel

6. Medical Radiation (Radiotherapy and Medical Imaging)

7. Radon Gas

8. Conclusion

Glossary

List of Abbreviations

Section VIII. Bystander and Transgenerational Effects – Epigenetic Perspective

Chapter 34. Sins of Fathers Through a Scientific Lens: Transgenerational Effects

1. Introduction

2. Radiation-Induced Genome Instability

3. Mechanisms of Transgenerational Effects: Epigenetic Changes

4. Transgenerational Effects Caused by Other Mutagens

5. Conclusions and Outlook

Glossary

List of Abbreviations

Chapter 35. Genomic Instability and the Spectrum of Response to Low Radiation Doses

1. Introduction to Low Radiation–Dose Effects

2. Concept of Uncertainty

3. Search for Determinators

4. Conclusions

Glossary

List of Acronyms and Abbreviations

Chapter 36. Transgenerational Genome Instability in Plants

1. Introduction

2. Genome Stability May Depend Upon the Choice of the DSB DNA-Repair Pathway

3. Epigenetic Regulation of Plant Genome Stability

4. Transgenerational Responses

5. Possible Mechanisms Involved in the Regulation of Transgenerational Inheritance of Stress Memory

6. Concluding Remarks

Glossary

List of Abbreviations

Chapter 37. Methods for the Detection of DNA Damage

1. Introduction

2. The Detection of DSBs in Cultivated Mammalian Cells and Tissues

3. γH2AX in Biodosimetry and Clinical Assays

4. Comet Fluorescence In Situ Hybridization (Comet-FISH) in the Detection of Different Types of DNA Damage

5. Methods for Studying DNA Repair After UV

6. Conclusions

Glossary

List of Abbreviations

Chapter 38. Conserved and Divergent Features of DNA Repair: Future Perspectives in Genome Instability Research

1. An Overview and Comparison of DNA-Repair Pathways in Different Organisms

2. Recent Advances and Future Directions in DNA Repair

3. Future Directions in Research on DNA Repair, Genome Stability, and Cancer

4. Future Perspectives in DNA-Editing Technologies

Glossary

List of Abbreviations

Index

Translational Epigenetics Series

Trygve O. Tollefsbol, Series Editor

Transgenerational Epigenetics

Edited by Trygve O. Tollefsbol, 2014

Personalized Epigenetics

Edited by Trygve O. Tollefsbol, 2015

Epigenetic Technological Applications

Edited by Y. George Zheng, 2015

Epigenetic Cancer Therapy

Edited by Steven G. Gray, 2015

DNA Methylation and Complex Human Disease

By Michel Neidhart, 2015

Epigenomics in Health and Disease

Edited by Mario F. Fraga and Agustin F. Fernández, 2015

DNA Biomarkers and Diagnostics

Edited by José Luis García-Giménez, 2015

Drug Discovery in Cancer Epigenetics

Edited by Gerda Egger and Paola Arimondo, 2015

Medical Epigenetics

Edited by Trygve O. Tollefsbol, 2016

Chromatin Signaling

Edited by Olivier Binda and Martin Fernandez-Zapico, 2016

Copyright

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List of Contributors

A. Anikin,     University of Calgary, Calgary, AB, Canada

J.N. Barr,     University of Leeds, Leeds, United Kingdom

A. Bilichak,     Agriculture and Agri-Food Canada, Lethbridge, AB, Canada

D. Bonatto,     Federal University of Rio Grande do Sul, Porto Alegre, Brazil

L. Boteva,     The University of Edinburgh, Edinburgh, United Kingdom

Y. Cheng

University of British Columbia, Vancouver, BC, Canada

Xiamen University, Xiamen, P.R. China

J. Cobb,     University of Calgary, Calgary, AB, Canada

J. de Faria Poloni,     Federal University of Rio Grande do Sul, Porto Alegre, Brazil

F. Eudes,     Agriculture and Agri-Food Canada, Lethbridge, AB, Canada

R. Fearns,     Boston University School of Medicine, Boston, MA, United States

B.C. Feltes,     Federal University of Rio Grande do Sul, Porto Alegre, Brazil

L.R. Ferguson,     University of Auckland, Auckland, New Zealand

D.V. Firsanov

Institute of Cytology of the Russian Academy of Sciences, Saint-Petersburg, Russia

Nikiforov Russian Center of Emergency and Radiation Medicine of the EMERCOM of Russia, Saint-Petersburg, Russia

Y. Gao,     University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

C. Gelot,     Université Paris-Saclay, Villejuif, France

N. Gilbert,     The University of Edinburgh, Edinburgh, United Kingdom

R.M. Golsteyn,     University of Lethbridge, Lethbridge, AB, Canada

A. Golubov,     University of Lethbridge, Lethbridge, AB, Canada

V. Gomez,     University College London, London, United Kingdom

A.A. Goodarzi,     University of Calgary, Calgary, AB, Canada

R. Gundogdu,     University College London, London, United Kingdom

T. Hatkevich,     University of North Carolina, Chapel Hill, NC, United States

A. Hergovich,     University College London, London, United Kingdom

W. Hernandez-Sanchez,     Case Western Reserve University, Cleveland, OH, United States

M. Hetman,     University of Louisville, Louisville, KY, United States

J.K. Holsclaw,     University of North Carolina, Chapel Hill, NC, United States

P. Hsieh,     National Institutes of Health, Bethesda, MD, United States

T.C. Humphrey,     University of Oxford, Oxford, United Kingdom

T. Izumi,     University of Kentucky, Lexington, KY, United States

R.E. Jones,     University of Oxford, Oxford, United Kingdom

F. Jönsson,     University of Witten/Herdecke, Witten, Germany

I. Kovalchuk,     University of Lethbridge, Lethbridge, AB, Canada

O. Kovalchuk,     University of Lethbridge, Lethbridge, AB, Canada

Y. Kulaberoglu,     University College London, London, United Kingdom

T. Le-Guen,     Université Paris-Saclay, Villejuif, France

A.F.C. Lopes,     University of Cologne, Cologne, Germany

B.S. Lopez,     Université Paris-Saclay, Villejuif, France

I. Mellon,     University of Kentucky, Lexington, KY, United States

M. Merrifield,     University of Lethbridge, Lethbridge, AB, Canada

J.-E. Messling,     University of Cologne, Cologne, Germany

V.M. Mikhailov,     Institute of Cytology of the Russian Academy of Sciences, Saint-Petersburg, Russia

K.N. Miyamoto,     Federal University of Rio Grande do Sul, Porto Alegre, Brazil

P. Moskwa,     Medical University of Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany

C. Mothersill,     McMaster University, Hamilton, ON, Canada

E. Mutter-Rottmayer,     University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

T. Negishi,     Okayama University, Okayama, Japan

D.D. Pearson,     University of Calgary, Calgary, AB, Canada

M. Pereira-Gómez,     Universitat de València, Paterna, Spain

S. Ragu,     Université Paris-Saclay, Villejuif, France

M. Renaud-Young,     University of Calgary, Calgary, AB, Canada

K. Riabowol,     University of Calgary, Calgary, AB, Canada

M. Rieckher,     University of Cologne, Cologne, Germany

J. Risso,     Universitat de València, Paterna, Spain

K.D. Robertson,     Mayo Clinic, Rochester, MN, United States

R. Sanjuán,     Universitat de València, Paterna, Spain

B. Schumacher,     University of Cologne, Cologne, Germany

J. Sekelsky,     University of North Carolina, Chapel Hill, NC, United States

C. Seymour,     McMaster University, Hamilton, ON, Canada

C. Sidler,     ETH Zürich, Zürich, Switzerland

L.V. Solovjeva,     Institute of Cytology of the Russian Academy of Sciences, Saint-Petersburg, Russia

M.P. Svetlova,     Institute of Cytology of the Russian Academy of Sciences, Saint-Petersburg, Russia

L.H. Swift,     University of Lethbridge, Lethbridge, AB, Canada

S. Tateishi,     Kumamoto University, Kumamoto, Japan

D.J. Taylor,     Case Western Reserve University, Cleveland, OH, United States

C. Vaziri,     University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

B. Wang,     University of Lethbridge, Lethbridge, AB, Canada

W. Wei,     Massachusetts General Hospital Cancer Center, Boston, MA, United States

A.B. Williams,     University of Cologne, Cologne, Germany

M. Xu,     Case Western Reserve University, Cleveland, OH, United States

M. Yang,     National Institutes of Health, Bethesda, MD, United States

D. Zhou,     Mayo Clinic, Rochester, MN, United States

Introduction

We have made our best efforts to collect chapters covering research on DNA repair and genome stability/instability in various species belonging to all domains of life. Moreover, we thought it would be very beneficial to give an epigenetics perspective to understanding of the regulation of DNA repair and genome stability. Therefore, several chapters discuss the role of the environment in DNA repair and genome stability. We also attempted to summarize genome changes during the evolution of new species, with an emphasis on randomness and nonrandomness of changes in various species. Finally, we have attempted to compare DNA-repair pathways in different organisms and to summarize what can be potentially done in the future to know more about DNA repair and genome stability.

The opening chapter (Chapter 1) of this book is Genome stability: an evolutionary perspective by Igor Kovalchuk. In this chapter, he discusses various aspects of genome evolution, by presenting the case of both Lamarckian and Darwinian models of evolution, describing the role of the environment in evolution and in particular in genome evolution, and explaining how the genetic and epigenetic components of DNA repair and genome stability have evolved. The chapter also touches upon some interesting controversies over the randomness or nonrandomness of changes in the genome, as well as the rate of DNA repair in various genomic regions in the same or different species.

In the next several chapters, we discuss the aspects of DNA repair and genome stability across all domains of life. Specifically, the chapters by John Barr and Rachel Fearns, Rafael Sanjuán, Marianoel Pereira-Gómez, and Jennifer Risso describe DNA-repair mechanisms and the aspects of genome instability in RNA and DNA viruses, respectively. In the chapter covering genome stability in RNA viruses (Chapter 2), Barr and Fearns describe how RNA viruses are able to withstand challenge with antiviral drugs and cause epidemics in previously exposed human populations. They also describe an extraordinary degree of genetic heterogeneity in RNA viruses; RNA viruses exist not as single genotypes but as swarms of related variants, and this genomic diversity is an essential feature of their biology. It appears that RNA viruses have a variety of mechanisms that act in combination to determine their genetic heterogeneity, such as polymerase fidelity, error-mitigation mechanisms, genomic recombination, and different modes of genome replication. Finally, Barr and Fearns present the evidence that some RNA viruses operate close to a threshold where the polymerase error rate has evolved to maximize the availability of the possible sequence space, while avoiding the accumulation of lethal deleterious mutations.

Describing genome stability of DNA viruses (Chapter 3), Sanjuán and colleagues show that DNA viruses can exhibit rapid sequence changes that are often found in loci involved in dynamic host–virus interactions. In particular, they describe that DNA viruses are capable of promoting genomic instability of certain specific genes, thus boosting the diversity where it is needed. Among specific mechanisms maintaining the viral diversity are diversity-generating retro-elements, a recombination-driven gene amplification, and DNA editing by host-encoded deaminases.

The second section of the book describes DNA repair and genome instability in prokaryotes. This section includes chapters by Ashley Williams and colleagues in which they compare genome stability of bacteria and archaea (Chapter 4), and show the role of the environment in bacterial mutagenesis (Chapter 5). Jan-Erik Messling and Ashley B. Williams demonstrate that through a careful regulation, prokaryotic cells employ the complex and sophisticated pathways that maintain a balance between genome stability and instability to allow not only self-preservation in future generations but also a genetic innovation for continued adaptation and evolution. They discuss the basic mechanisms that bacteria and archaea use to limit genome instability and also compare different approaches used by these two domains of life to face assaults by both endogenous and exogenous forces. In Chapter 5, Ashley Williams discusses various sources of genome instability in bacteria, including stress responses, mutator genotypes, recombination, specialized genetic sequences, and mobile genetic elements. They also show the consequences of these different pathways, with a specific focus on those ones that impact pathogens and their interactions with their hosts. In Chapter 6, Adnrey Golubov describes an ancient bacterial immune system—CRISPR/Cas9. He discusses the history of research on CRISPR/Cas9, the genetic structure of this system and its molecular mechanisms of action and regulation. The discovery of CRISPRs and a path to its application in genetic engineering is an example of a rare breakthrough that revolutionizes science and technology. It is not surprising that in 2015, the CRISPRs technology has been named one of the breakthrough technologies of the year by Science magazine.

The third section of this book covers genome stability of unicellular eukaryotes by presenting two chapters which address genome stability in ciliates by Franziska Jönsson (Chapter 7) and genome stability in yeasts by Rebecca Jones and Timothy Humphrey (Chapter 8). Ciliates are unique organisms as far as genome stability is concerned because they involve massive developmentally regulated changes in the genome structure driven by noncoding RNAs (ncRNAs). Franziska Jönsson compares the macronuclear development of two distantly related ciliate classes to show how the nuclear organization reflects different types of adaptation and regulation mechanisms exhibiting the power of ncRNAs in genome evolution.

In Chapter 8, Rebecca Jones and Timothy Humphrey describe the details of double-strand break (DSB) repair pathways in yeast.

Section 4 of the book focuses on DNA repair and genome stability in multicellular eukaryotes, excluding mammals. In Chapter 9, Julie Korda Holsclaw, Talia Hatkevich, and Jeff Sekelsky describe the major mitotic DSB-repair pathways, homologous recombination (HR) repair, and end joining in Drosophila. Specifically, they discuss the key regulatory mechanisms of meiotic recombination that promote repair of meiotic DSBs in the form of crossovers and present a novel model recently introduced for meiotic recombination in Drosophila. Research in Drosophila has been complemented by Chapter 10 presented by Tomoe Negishi who describes the role of mismatch repair (MMR) activities in genome stability of Drosophila, reviewing the role of MMR in meiotic recombination, mitotic DNA replication, and the induction of mutations.

In Chapter 11, Matthias Rieckher, Amanda Franqueira Lopes, and Björn Schumacher provide an overview of DNA repair and DNA-damage response mechanisms in Caenorhabditis elegans and various methodologies that have been employed to gain an insight into metazoan genome stability.

Chapters 12 and 13 cover research in plants. In Chapter 12, Andriy Bilichak provides a review of the most important DNA-repair pathways in plants that work together during plant development for an efficient maintenance of genome stability and plant survival, whereas in Chapter 13, Andriy Bilichak and Francois Eudes describe the use of three modern genome-editing technologies, zinc-finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeats/Cas9, that are used for permanent modifications of plants. The authors present an overview of the discovery of each of the technologies, their benefits, limitations, and their potential effectiveness for the future development of genetic engineering in plants.

Section 5 of the book is the largest one covering details of various DNA-repair pathways utilized by mammals to repair DNA. The section begins with Chapter 14 by Valenti Gomez and Alexander Hergovich focusing on the regulation of the mammalian cell cycle in the context of DNA-damage signaling and DNA damage–repair mechanisms. The authors also discuss some molecular aspects in the context of diseases. In Chapter 15, Yavuz Kulaberoglu, Ramazan Gundogdu, and Alexander Hergovich provide an overview of an important role of p53, p21, and p16 in cell-intrinsic checkpoints as well as signaling and repair responses to prevent genome instability. They also discuss the significance of these tumor suppressors in the context of cancer and DNA-damaging therapies designed to specifically target tumor cells.

Further details of DNA repair and genome stability in mammals are presented by Cyrus Vaziri, Satoshi Tateishi, Elizabeth Mutter-Rottmayer, and Yanzhe Gao in Chapter 16 that describes the role of RAD18 in DNA replication and post-replication repair (PRR). The authors review the mechanisms of RAD18 activation in response to DNA damage, its participation in translesion DNA synthesis and template switching, and the basis for the integration of RAD18 activity with other elements of the DNA-damage response and the cell cycle. The authors also discuss the potential impact of RAD18 on genome stability and tumorigenesis.

In Chapter 17, Tadahide Izumi and Isabel Mellon introduce the history and concepts of DNA-excision repair, discuss types of DNA damage processed by base-excision repair (BER) and nucleotide-excision repair (NER), and describe the repair mechanisms. The authors present a recent evidence indicating that DNA-damage and excision-repair proteins are key signal transducers and play critical roles in DNA-damage responses and communications between nuclei and mitochondria.

In Chapter 18, Mingzhang Yang and Peggy Hsieh summarize current knowledge of the mechanism of MMR in mammalian cells, its role in DNA-damage signaling, and its contribution to the maintenance of genome stability and tumor suppression.

In Chapter 19, Patryk Moskwa introduces nonhomologous end joining (NHEJ) repair pathways of DSBs and their components in mammals. He covers the details of their function, structure, binding partners, and possible regulations.

In Chapter 20, Camille Gelot, Tangui Le-Guen, Sandrine Ragu, and S. Bernard summarize different molecular mechanisms of HR in mammals. They discuss the role of HR in DNA DSB repair, the reactivation of arrested replication forks, and their consequences (radiation sensitivity, meiosis, and the application in genome manipulation). The authors propose a model for the choice of the DSB-repair pathway that functions in two steps: ssDNA resection versus the canonical NHEJ pathway and alternative end-joining pathway versus HR on resected DNA. Finally, the authors present the role of HR in the molecular evolution of multigene families in the process of concerted evolution.

In Chapter 21, the role of telomere maintenance in genome stability is introduced by Wilnelly Hernandez-Sanchez, Mengyuan Xu, and Derek J. Taylor. The authors describe recent advances that suggest the involvement of dysfunctional telomeres or the improper regulation of telomerase activity in the development of a host of human diseases that include premature aging syndromes, bone marrow failures, and cancer.

In Chapter 22, Lucy H. Swift and Roy M. Golsteyn describe the relationship between checkpoint adaptation and mitotic catastrophe in cancer cells. They review factors that contribute to checkpoint adaptation, such as the cell cycle, checkpoints, mitotic catastrophe, and cell death, and describe their relationship to genome instability. The authors suggest that distinguishing checkpoint adaptation from apoptosis will aid in the study of how genome instability is generated and amplified in cancer cells.

The following three chapters of this section introduce the role of epigenetic components in the regulation of genome stability. Chapter 23 by Lora Boteva and Nick Gilbert describe an indispensable role of the chromatin structure and nuclear organization in DNA repair and the maintenance of genome stability. The authors present a modern view in which genome stability aims to integrate the influence of fundamental cellular processes such as transcription and replication with the chromatin context in order to get a better understanding of the processes that shaped the human genome. In Chapter 24, Dan Zhou and Keith Robertson describe the role of DNA methylation in the maintenance of genome stability. The authors describe how DNA methylation and DNA methyltransferases assist in recognizing mismatches, while also contributing to genome stability by regulating MMR gene transcription. The authors show how intensive DNA methylation at heterochromatin repeats stabilizes such domains from their translocation and undesired spreading, ensuring the appropriate functions of centromeres and telomeres as well as the genetic integrity. Finally, in Chapter 25, Igor Kovalchuk explains how ncRNAs play direct and indirect roles in the regulation of genome stability.

Section 6 covers human genetic diseases and conditions associated with genome instability. In Chapter 26, Bruno César Feltes, Joice de FariaPoloni, Kendi Nishino Miyamoto, and DiegoBonatto describe human diseases associated with genome instability. The authors review the repair machineries underlying rare genetic diseases and different types of cancer. Chapters 27 and 28 present genome instability in cancer. Specifically, in Chapter 27, Wei Wei, Yabin Cheng, and Bo Wang provide a comprehensive coverage of various DNA-repair pathways and their contribution to almost all types of human malignancies. In this chapter, they describe the current understanding of defects in DNA-repair pathways in the development of cancer as well as DNA-repair pathway targeting as a potential strategy for cancer therapy. In Chapter 28, Margaret Renaud-Young, Karl Riabowol, and Jennifer Cobb describe the epigenetic regulation of the cell cycle and DNA repair in cancer. Since the ability of proteins in different repair pathways to find and repair lesions is critical in the maintenance of genome stability and prevention of cancer, work in the chromatin field is particularly important to understand the chromatin dynamics during DNA-damage recognition and repair. The authors summarize the factors regulating chromatin changes that are critical in mediating the repair of DNA damage.

Chapter 29 by Corinne Sidler introduces us to the world of aging and the role that genome instability plays in this process. The author presents several lines of evidence showing that the accumulation of unrepaired DNA damage and the resulting genomic instability play a central role in promoting aging.

In Chapter 30, Michal Hetman describes the function of the nucleolus in the DNA-damage response and the genomic (in)stability in the nervous system. In this chapter, the mechanisms and potential consequences of nucleolar involvement in the genomic instability are discussed in detail.

Section 7 focuses on the effects of the environment on genome stability. In Chapter 31, Lynnette Ferguson describes the association between variations in the diet, changes in the level of free radicals, and DNA damage. The author discusses how diets enriched with various nutrients and phytochemicals may provide DNA protection. Furthermore, the author discusses how polymorphisms in genes for nutrient uptake, metabolism, and excretion can determine the optimal dietary intake for an individual. In Chapter 32, Olga Kovalchuk describes the role of chemicals and chemical mutagenesis in DNA repair and genome instability. In Chapter 33, Aaron Goodarzi, Alexander Anikin, and Dustin Pearson describe how the ionizing radiation (IR) from environmental sources affects human health. They review the primary sources of human IR exposure, including a nuclear attack, civilian nuclear disasters, aerospace travel, medical radiation (radiotherapy and computed tomography imaging), and radon gas inhalation, and their health consequences.

Section 8 covers epigenetic perspective of bystander and transgenerational effects. In Chapter 34, Matt Merrifield and Olga Kovalchuk introduce the concept of transgenerational response in animals and describe how this phenomenon is controlled by epigenetic components. They specifically focus on the effect of IR, describing direct and indirect effects and introducing the concept of bystander and nontargeted effects of IR. In Chapter 35, Carmel Mothersill and Colin Seymour discuss whether low doses of radiation are harmful or good. The authors present some of the reasons for the controversy and mistrust. They propose that we as humans need to accept uncertainty; they also suggest some approaches to developing protection frameworks which might be more fruitful.

In Chapter 36, Igor Kovalchuk introduces the concept of transgenerational response in plants. The author describes changes that occur in response to stress at the level of genome stability and epigenome regulation and discusses the role of transgenerational response to stress in plants for the regulation of genome stability.

Chapter 37 by Firsanov, Solovjeva, Mikhailov, and Svetlova presents various methods that can be used to analyze DNA damage and changes in genome stability. They pay a special attention to immunological methods of monitoring DNA damage and repair in single cells.

Finally, Chapter 38 by Igor Kovalchuk presents a logical summary of the book Conserved and divergent features of DNA repair. Future perspectives in genome-instability research. In this chapter, the author describes differences in DNA repair among bacteria, archaea, and eukarya and suggests potential future directions in DNA-damage repair and genome-stability research.

Igor Kovalchuk

Olga Kovalchuk

Chapter 1

Genome Stability

An Evolutionary Perspective

I. Kovalchuk     University of Lethbridge, Lethbridge, AB, Canada

Abstract

The genetic material in the form of DNA or RNA determines the inherited characteristics of every given organism or species. Despite the diversity of genetic variants in a population of species, there is a great conservation of the sequence of genetic material. The stages of development, the structure and function of cells and tissues, and the interaction with the environment are all determined by the genetic makeup of an organism. Therefore, the preservation of genetic material is of an utmost importance for any organism. It is thus not surprising that mutations are very rare. At the same time, why do we have such a diversity of species, genome sizes, and genome structures? In this chapter, we discuss certain aspects of genome evolution and genome stability, the effect of genetic and epigenetic components, and the maintenance of genome stability as well as a certain allowed level of genome instability and the role of the environment in this process.

Keywords

Epigenetics; Evolution; Genetic and epigenetic components; Genome stability; The environment

Chapter Outline

1. Introduction

2. Evolution Theories and My Reflection on Them

3. The Role of Symbiosis in Genome Evolution

3.1 Changes in the Structure of the Organellar Genome Over Time

3.2 Mutation Rates in Organellar Genomes and Adaptive Evolution

3.3 Symbiotic Interactions Between Viruses, Prokaryotes, and Eukaryotes: The Role of Transposable Elements

4. Fixation of a Mutant Allele in a Population

5. Evolution of Mutation Rates

5.1 Evolution of Somatic Mutation Rates

6. Genome Instability: Is It Random?

6.1 A Bias in Mutations in Different Genomic Regions

7. Genome Evolution May Start From Changes at the Level of DNA Methylation or Chromatin Modification

8. Conclusion

Glossary

List of Abbreviations

References

1. Introduction

Genome stability is a feature of every organism to preserve and faithfully transmit the genetic material from generation to generation or from one somatic cell to another. This includes an error-free replication of genetic material (DNA or RNA) and the repair of replication mistakes or damaged DNA/RNA (see the corresponding chapters in this book). In contrast, genome instability covers a broad range of topics referring to an increased rate of DNA damage and the associated mutations, the role of potential direct and indirect mutagens, the role of external and internal factors contributing or mitigating such instability, and so on.

In this chapter, we discuss genome stability/instability from the perspective of evolution, and specifically genome evolution. Genome evolution refers to changes in the genome structure or genome size over time. Usually, such changes are changes in the DNA (RNA) sequence that are passed on to the progeny and the accumulation/fixation of such genetic variants or their rejection in a population. Genome evolution is normally discussed in the context of evolution of new species, and thus it is closely associated with the appearance of new traits, new phenotypical and morphological features, and so on.

Considering that new traits and phenotypes may develop due to epigenetic changes, it is plausible to think that genome evolution in part also involves changes in genome structure due to epigenetic modifications. In contrast to genetic changes that include mutations in the DNA sequence, epigenetic changes involve heritable but potentially reversible changes in gene expression due to changes in DNA methylation and histone modifications, among others.

Hence, how does the genome actually evolve? What are driving forces in genome evolution? Does evolution have the spontaneous and random nature? Is it actually directed and driven by changes in the external and internal environment? In the following, we contrast Darwin’s and Lamarck’s views on evolution and discuss the mechanisms that impact rate of evolution and the crucial role of the environment, especially as far as evolution of genome is concerned.

2. Evolution Theories and My Reflection on Them

The first theory of evolution was proposed about 200  years ago by a prominent French biologist Jean-Baptiste Lamarck (1744–1829). Although he was the first who built a somewhat coherent theory of evolution, he initially referred to the process as transformation, explaining that organisms transform as a result of a new need that continues to make itself felt. Evolution, according to Lamarck, was also the process in which less complex species evolve into more complex ones. Lamarck’s understanding of evolution was summarized by him in four major laws. He used these laws to explain the two forces that he believed comprise evolution; a force driving animals from simple to complex forms, and a force adapting animals to their local environments. He formulates:

Law 1: Life, by its own forces, continually tends to increase the volume of every body which possesses it and to enlarge the size of its parts up to a limit which it brings about itself. Law 2: The production of a new organ in an animal body results from the appearance of a new want or need, which continues to make itself felt, and from a new movement which this want gives birth to and maintains. Law 3: The development of the organs and their strength of action are constantly in proportion to the use of these organs. Law 4: All that has been acquired, impressed upon, or changed in the organization of individuals during the course of their life is preserved by generation and transmitted to the new individuals that come from those which have undergone those changes.

Let’s briefly discuss all four laws. Law 1 suggests that in the process of evolution organisms become larger; by this Lamarck also meant—more complex. Although there is some evidence that in the process of evolution organisms increased in size, primarily on transition to multicellularity, there is no evidence that larger organisms are more complex in general. Also, there is no real correlation between the size and complexity of an organism; although we must admit that it is difficult to define how complex certain species are. However, there appears to be evidence that during the history of life, the complexity of organisms increased. Hence, the law may stand with limitations. Law 2 postulates that an organism can change when there is a need or want. The need to change when the environment changes is understandable, but what Lamarck meant here was that organisms could drive their changes in the direction they want. This is definitely an overstatement, as there is no evidence that desire to change plays any role in evolution. Thus, it is difficult to defend this law, but we come back to it later on in the review. Law 3 is a famous law of use and disuse. There are a lot of interpretations of this law and a lot of debates around it. To me, it suggests that if a certain trait is constantly required (used) in a given environment, it becomes prominent and fixed in the progeny, whereas a trait that is not used (it may have been important in the previous environment), it slowly disappears upon transition from progeny to progeny. Although it seems that Lamarck links the law of use and disuse to the law of want and need, the law in my opinion stands, as use or disuse of certain traits due to the presence or absence of environment that calls upon them may result in appearance or disappearance of this trait in evolution. Law 4 is known as inheritance of acquired characteristics. Lamarck suggested that every change acquired by an organism is passed on to the progeny. We have plenty of evidence that this is not true, but many articles, especially in the past 10–15  years, clearly demonstrate that the acquired characteristics can be inherited. We discuss this later on in the review. The law stands in part. Therefore, as it appears, no matter how simplistic and naive the postulates may have been, they have a lot of merit. Lamarck definitely deserves a credit for recognizing the environment as a shaping force of evolution.

What about Charles Darwin’s theory of evolution? There is no doubt that Darwin’s work was influenced by Lamarck’s work. Darwin summarized his voyage on the Beagle into the book On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life [1]. Darwin’s theory of evolution suggested that organisms in a given population evolve through a process of natural selection. His main idea was that among individuals within a population there are always those ones who are fitter than others, and fitter organisms have higher chances to reproduce and leave more progeny, passing their heritable traits on to the next generation. As the environment changes due to the migration of a population of a given species or due to some unpredictable changes in the environment such as large temperature shifts, changes in water availability, or the appearance of competitors, a certain part of population that is more fit for the new environment adapts passing its genes/alleles on to the progeny, and eventually even may become a separate species. Seeing undisputable role of environment in the process of evolution, Darwin accepted a version of the inheritance of acquired characteristics proposed earlier by Lamarck. This is perhaps due to the fact that genetics and genes per se were not known to Darwin, and he had a difficult time coming up with a detailed mechanism for passing on traits from one generation to the next.

Evolution by Natural Selection proposed by Darwin did not transform much from the time he published his theory, but it was completed by additional knowledge of genes and genetics, thus transforming into the currently accepted modern evolutionary synthesis (MES) (also referred to as modern synthesis). One of the descriptions of MES was done by Futuyma. He writes:

The major tenets of the evolutionary synthesis, then, were that populations contain genetic variation that arises by random (i.e., not adaptively directed) mutation and recombination; that populations evolve by changes in gene frequency brought about by random genetic drift, gene flow, and especially natural selection; that most adaptive genetic variants have individually slight phenotypiceffects so that phenotypic changes are gradual (although some alleles with discrete effects may be advantageous, as in certain color polymorphisms); that diversification comes about by speciation, which normally entails the gradual evolution of reproductive isolation among populations; and that these processes, continued for sufficiently long, give rise to changes of such great magnitude as to warrant the designation of higher taxonomic levels (genera, families, and so forth) [2].

First, whereas Darwin’s theory of evolution suggested natural selection as the main (the only?) driving force, MES proposed several other possibilities, including genetic drifts and gene flow, although still giving the main emphasis to natural selection. Second, MES recognizes that traits are passed on from one generation to another in a discrete form of inheritance—genes. It further postulates that potential variants among individuals within the same species are due to the presence of multiple alleles of the same gene. Third, MES postulates that evolution is a gradual process, where small changes accumulate at the gene level becoming big changes leading to a speciation event. Therefore, macroevolution is, strictly speaking, multiple events of microevolution.

Understanding the process of evolution and what it involves still triggers many debates and disagreements that arise primarily from different perspectives, depending on whether you are a geneticist, a naturalist, a population biologist, an epigeneticist, or a paleontologist. It is still not clear whether evolution has gradual nature—whether macroevolution is a result of multiple steps of microevolution. Most of the paleontological findings suggest that speciation events occur rapidly. In 1972, the theory of punctuated equilibrium was put forward by Gould and Niles Eldredge; they proposed that evolutionary changes occur in relatively rapid spurts coincident with an increase in speciation rates [3]. They argued that such disruptions of equilibrium occur when a selective pressure is increased and when organisms adapted to a particular environment are no longer able to cope with the changing environment.

The appearance of new species may require several steps of microevolution. Since this is a continuous process, we hardly can trace the beginning and the end of the evolution process between, say, species A and B. Heterogeneity of individuals in a large population of certain species is already an initial step of microevolution, as a large pool of variations allows the population to acquire certain beneficial mutations that is favored in a certain environment much faster. Species are defined in many different ways. One definition is that they are a large group of individuals that carry similar phenotypic characteristics capable of interbreeding and giving rise to the fertile progeny. The ability to interbreed is the most important part of this definition. Therefore, until different populations of the same species are unable to interbreed, they are the same species, no matter how large the differences in their genetic material are. Is this actually true?

The analysis of taxonomic trees and the actual ability of certain species to interbreed and give rise to a viable progeny gave surprising results. In animals, less than 40% of animal taxa and less than 70% plant taxa represent reproductively independent lineages [4]. These data suggest that the definition of species as those that are incapable of interbreeding is at least outdated.

3. The Role of Symbiosis in Genome Evolution

As species do not live in isolation and constantly interact with each other, it is not surprising that they have learned to coexist in parasitic, commensalistic, and mutualistic ways. Altogether, such coexistence is referred to as a symbiotic interaction, although some scientists still consider symbiosis as a mutualistic relationship. Symbiosis had a great influence on evolution, including genome evolution. The very appearance of eukaryotic organisms is believed to be the result of symbiotic relationships between aerobic and anaerobic bacteria. Chloroplasts and mitochondria as well as possibly peroxisomes, flagella, cilia, centrioles, and maybe even the nucleus itself may have been independent organisms at one point, coexisting inside of a larger bacterial ancestor. The endosymbiotic theory of the appearance of eukaryotic organisms is supported by several lines of evidence [5].

First of all, the mitochondrial and chloroplast genomes resemble the genomes of some of currently existing bacteria; sequences in mitochondria have a similarity to alphaproteobacteria, whereas sequences of chloroplasts resemble those of cyanobacteria [6]. Second, as expected, there are organisms alive today that are in symbiotic relationships and may be in transition to becoming a new form of multicellular organisms. Such organisms are called the living intermediates. For example, the giant multinucleated protist amoeba Pelomyxa uses aerobic bacteria instead of mitochondria for aerobic respiration [7]. Also, the organisms such as corals, clams, and some Paramecium species host algae cells. Each coral polyp has a zooxanthellae algae cell within itself that carries out photosynthesis. Some clam species have a special type of cells known as iridocytes; microscopic towers of algae cells grow under iridocytes, resembling the stack of grana in chloroplasts [8]. The role of iridocytes is to filter the wavelengths that the algae prefer. In both described cases, algae cells gain protection by sharing the product of photosynthesis with host cells.

3.1. Changes in the Structure of the Organellar Genome Over Time

The mitochondrial and chloroplast genomes have undergone substantial changes since the time they have been bacterial organisms, but they have retained a circular structure characteristic of prokaryotic organisms, and genes located in them in most cases lack introns, unlike the nuclear genomes. Most of the chloroplast genomes are about 150  kb in size represented as a single circular molecule, although in some rare cases, for example, in dinophytic algae, the chloroplast genome is distributed over as many as 40 small plasmids, each carrying only several genes [9]. Through the process of evolution, the chloroplast genomes lost many genes either due to gene elimination or gene transfer to the nuclear genome, the process known as an endosymbiotic gene transfer. As a result, on average, chloroplasts contain fewer than 100 genes, much less than the original number of genes (likely between 1000 and 5000) in endosymbiotic bacteria such as cyanobacteria. Plant nuclei contain many genes originating from chloroplasts, perhaps as many as 10–15%, with Arabidopsis having as much as 18% of all protein-coding genes stemming from the chloroplast [10].

Was the reduction of gene number in chloroplasts a gradual process, or was it a result of several massive rapid changes? Although there is no clear answer, it is believed that most of the genes were transferred early on [11]. However, one of the reports suggests that at least some endosymbiotic gene transfers may have occurred in land plants fairly recently. For example, the gene rpl22 encoding the chloroplast ribosomal protein CL22 is present in the chloroplast genome of all plants examined except legumes, while a functional copy of rpl22 is located in the nucleus of the legume pea [12], suggesting that the transfer occurred after speciation event in legumes.

Although it is commonly accepted that chloroplasts lost genes to the nucleus, there is very little evidence that they gained genes from the nucleus or from the environment. One such example includes the horizontal gene transfer (horizontal transfer, HT) of four genes between Bacteroides species and minicircles of plastid genomes of dinoflagellate species Ceratium horridum and Pyrocystis lunula [13].

Mitochondrial genomes are much more complex and diverse as compared to plastid genomes. They can be either circular as in most multicellular animals, linear as in fungi, protozoa, and algae, or a combination of circular and linear chromosomes as in many plants. While animal mitochondrial genomes are fairly small, less than 20  kb in size, plant genomes are much larger, between 200  kb and 2000  kb. In animals, most of the genes are intronless, with coding regions representing over 90%, whereas in plants, many genes contain introns and only 10% of DNA represent coding regions. Cucumber has one of the largest mitochondrial genomes (∼1700  kb), and unlike most plant mitochondrial genomes, it has three circular chromosomes instead of one [14]. The smaller size of mitochondrial genomes in animals compared to plants can be due to the higher rate of endosymbiotic gene transfer in animals versus plants [15].

One of the theories explaining the relative compactness of organelle genomes is an advantage in the replication process. Smaller genomes replicate faster [15], allowing the organelle to divide faster and therefore to be overrepresented in the cytoplasm. Thus, organelles with smaller genomes may have had an advantage in a natural selection process.

3.2. Mutation Rates in Organellar Genomes and Adaptive Evolution

Do the organellar genomes still evolve? Do they evolve at the same rate in different species? In part this can be answered by the analysis of mutation rate in different organellar genomes. Plastid-bearing eukaryotes typically have lower rates of silent substitutions in plastid genomes versus mitochondrial genomes [16]; however, it is generally accepted that for land plants, the plastid and nuclear genomes have up to a 10-fold greater mutation rate than the mitochondrial genome. At the same time, several plants have higher point mutation rates in mitochondria than in plastid genomes [17,18].

In animals, the mitochondrial genome mutation rate is much higher than that in the nuclear genome [19]. In addition, the mutation rate in mtDNA varies greatly among different animals. Two major theories of such variations are the generation time and metabolic rate hypotheses. The generation time hypothesis suggests that short-lived species have a higher number of replication errors per a certain time unit (eg, a year) due to a higher number of DNA replication rounds. Obviously, this model only explains the difference in replication-dependent mutations, assuming that the replication error is constant across species [20]. The metabolic rate hypothesis expresses that the mitochondrial mutation rate is a reflection of metabolic rates and the level of produced free radicals, which are different in animals of different body mass [21]. This model may be applicable to all type of mutations, regardless of the replication rate.

The detailed analysis of nucleotide substitution rates at the gene encoding cytochrome b across 1696 mammalian species revealed a two orders of magnitude variation between the tested lineages [20]. It was found that cytochrome b third codon positions are renewed every 1–2  Myr in the fastest evolving mammals and over 100  Myr in slow-evolving ones. The authors further demonstrated that the generation time and metabolic rate hypothesis could not fully explain the data. It was suggested that mitochondrial mutation rates decrease in long-lived species, which is in agreement with the mitochondrialtheory of aging, which suggests that organisms age in part due to mutations accumulating in mitochondrial [20]. This finding also suggests that mitochondrial mutation rates may have the partial adaptive nature. A more substantial proof of the adaptive nature of mutations in mtDNA comes from the work of James et al. [22]. The authors used a pairwise comparison and computer algorithms for the mitochondrial genome sequence data from 500 animals and found the evidence that mitochondria generally experience a substantial level of adaptive evolution. In addition, they found some weak evidence that the level of adaptive evolution in mitochondria correlates with the effective population size (Ne).

3.3. Symbiotic Interactions Between Viruses, Prokaryotes, and Eukaryotes: The Role of Transposable Elements

Symbiotic interactions between viruses and prokaryotic or eukaryotic cells as well as between prokaryotes and eukaryotes continue to shape the genomes of modern species.

Horizontal transfer (HT)—the transfer of genetic material between asexually reproducing organisms—is one of the mechanisms shaping the genomes of various species. This is a common mechanism among prokaryotes that contains passive (transduction, transformation) and active (conjugation, transformation) ways of HT. In contrast, HT is relatively rare in eukaryotes, partially due to the presence of barriers such as the presence of a nuclear envelope and the separation of gametic and somatic cells in multicellular eukaryotes. Despite this fact, many HT events have been recorded, most of them giving a selective adaptive advantage [11]. HT events can include the transfer of nongenic regions, genes, and transposable elements (TEs). HT of TE has been documented to occur across multiple phylogenetic levels both within prokaryotes and eukaryotes (reviewed in Ref. [23]). In contrast to HT of genes or TEs within prokaryotic or eukaryotic species, HT between the domains of life is less common for both genes and TEs. Moreover, interdomain HT of genes is substantially more common than interdomain HT of TEs. Hundreds of cases of prokaryote-to-eukaryote gene HTs have been characterized (reviewed in Ref. [23]). Gilbert and Cordaux carried out a comprehensive search for various groups of prokaryotic insertion sequences in 430 eukaryotic genomes [23]. They have identified 80 sequences integrated in the genomes of 14 different eukaryotes, all belonging to four distinct phyla (Amoebozoa, Ascomycetes, Basidiomycetes, and Stramenopiles). Further analysis revealed that these insertions were relatively recent events.

TEs have been initially discovered in 1948 by Barbara McClintock, a Nobel Prize winner in 1983. From the time of their discovery in maize to current days, they continue to be a puzzle. It is still unclear whether they are parasitic elements or symbionts of prokaryotic and eukaryotic species (perhaps at least some of them). Regardless of a clear definition, TEs have a powerful effect on genomes and evolution. TEs are capable of shaping host genomes through insertions, deletions, and recombination.

They can be broadly divided into transposons, elements capable of excision and reinsertion (conservative transposition) or elements capable of making a DNA copy first (replicative transposition) and retrotransposons, elements that amplify in the genome through RNA intermediates and reverse transcription followed by reinsertion. TEs are abundant among many species in various domains of life. Eubacteria, for example, may contain up to 20% of transposons [24], although many species have a very small number of transposons, and most of them are believed to be recent insertions [25]. Archaea are also believed to be similar in this matter [26]. In eukaryotes, especially in multicellular eukaryotes, TEs occupy a much larger genomic area: 45% in humans [27] and up to 85% in maize [28].

If TEs behave as any other genetic element, they have to evolve as any other genomic region under a certain selection pressure. If they are deleterious to the genome (species), they should gradually disappear, whereas if they are beneficial, they should be fixed. The fact that TEs exist in abundance in nearly all lineages suggests that transposons are likely to be under a positive selection pressure. Lineages that have a large number of TEs activated in response to stress may have a great advantage over those that either do not have them or have mobile elements that are irresponsive to environmental pressures. The mobilization of TEs may result in beneficial mutations, no matter how rare they are. These rare advantageous mutations may balance the fitness cost associated with maintaining and propagating TEs. Despite certain differences in the TE structure and the mode of activation in prokaryotes and eukaryotes, TEs have the same properties, and nearly in all cases, they are regulated by environmental factors.

Does the rate of occurrence of TEs depend on the genome size or reproduction mode? It was shown that TEs accumulate much faster in species with a low population size such as multicellular eukaryotes as compared to prokaryotes that have a large population size [29,30]. A larger population size may allow a more efficient elimination of slightly deleterious insertions by natural selection (see later), whereas a smaller population size may allow to retain them longer. The work by Startek et al. suggests that TE accumulation is also more likely in asexual eukaryotic populations that are under the constant environmental pressure than in populations living in the normal stable environment [31]. Similarly, it was suggested that in bacteria, the genomic TE content might also