Genome Chaos: Rethinking Genetics, Evolution, and Molecular Medicine

Cover
Genome Chaos: Rethinking Genetics, Evolution, and Molecular Medicine
Copyright
Dedication
Preface
Acknowledgments
1 . From Mendelian Genetics to 4D Genomics
	1.1 Summary
	1.2 The Emergence of Genomics
		1.2.1 A Brief History of Genomics
		1.2.2 Genetics or Genomics?
		1.2.3 Fundamental Limitations of Traditional Genetics
	1.3 Diminishing Power of Gene-Based Genomics
		1.3.1 The Ignored Voice of Antigenetic Determinism
		1.3.2 The Rise and Fall of the Gene
		1.3.3 A Reality Check of the “Industry Gene” Concept
		1.3.4 Gene-Based 1D Genomics Is Not Enough
	1.4 New Genomic Science on the Horizon
		1.4.1 Time to Rethink Genetics and Genomics
		1.4.2 Crisis Created New Opportunities for Future Genetics/Genomics
		1.4.3 4D Genomics: the New Paradigm
2 . Genes and Genomes Represent Different Biological Entities
	2.1 Summary
	2.2 The Definition of the Genome
	2.3 “Parts Versus the Whole”: The Emergent Relationship (Which Challenges Reductionism)
	2.4 ReExamining Gene Theory Predictions
		2.4.1 Selfish Gene or Constrained Genome?
		2.4.2 Genomes Not Genes Define Biosystems
			2.4.2.1 There Are No Common Minimal Gene Sets in Nature
			2.4.2.2 Are Gene or Genome Alterations Mainly Responsible for Speciation?
	2.5 The Conflicting Relationship Between the Gene and the Genome
		2.5.1 Chromosomal Position and Loop Size: Overall Genomic Architecture Constrains Local Structures
		2.5.2 Gene Expression and Chromatin Loops: Chromatin Loop Domains Constrain Gene Function
		2.5.3 Loops/Chromosome Length and AT/GC Composition: Why Little Clarification Comes from the Highest Resolution
	2.6 Genome Context Determines Gene Function
	2.7 Action Needed
3 . Genome Chaos and Macrocellular Evolution: How Evolutionary Cytogenetics Unravels the Mystery of Cancer
	3.1 Summary
	3.2 SOS: We Need a New Conceptual Framework for Cancer Research
		3.2.1 Exceptions Versus the General Rule: The Chronic Myeloid Leukemia Story
			1. The Unique Evolution of CML
			2. Population Genomic Structure and Microenvironments Influence the Pattern of Cancer Evolution and Their Responses to Trea ...
			3. Heterogeneity and Treatment Response
			4. Unforeseeable Negative Impact of CML on Research Community
			5. Exceptions of Model Systems and the Reality of Cancer
		3.2.2 Cancer Genome Sequencing: The Results Challenge the Rationale
			3.2.2.1 Initial Goal and Controversy
			3.2.2.2 Major Discoveries and Surprises
				1. Validation of Known Cancer Gene Mutations
				2. There are far Fewer Newly Identified Driver Genes Than Expected
				3. Interesting Gene Mutation/Genomic Alteration Patterns
				4. Chromosomal-level Alterations are Overwhelming
				5. Multiple Levels of Genetic/Genomic/Epigenomic Landscapes
				6. The Landscape Dynamics During Cancer Progression and After Treatment
			3.2.2.3 The Ultimate Challenge to Current Cancer Theory
				1. Too Many Mutations, not Enough Common Drivers
				2. Disagree with the stepwise cancer model of accumulating gene mutations
		3.2.3 The Somatic Gene Mutation Theory Is No Longer Relevant
			3.2.3.1 Challenging the Obvious: Can a Few Key Gene Mutations Be the Molecular Basis of Carcinogenesis?
			3.2.3.2 Challenging the Concept of Sequential Accumulation of Gene Mutations in Cancer
			3.2.3.3 The Limitations of Searching for Hallmarks of Cancer
			3.2.3.4 Clinic Facts Do Not Support the Cancer Gene Mutation Theory of Cancer
		3.2.4 Increased Calls for New Cancer Theories
			3.2.4.1 Noted Competing Theories/Concepts
				1. Aneuploidy Theory
				2. Tissue Organization Field Theory
				3. Cancer Attractor Theory
				4. Theories Influenced by the Natural History of Evolution
				5. Theories Influenced by Developmental Biology and Epigenetics
				6. Theories Related to Genetic and Environmental Factors
			3.2.4.2 The Search for New Framework
	3.3 Genome Chaos: Rediscovery of the Importance of the Karyotype in Cancer
		3.3.1 Linking Incidental NCCAs to CIN and Evolutionary Potential
		3.3.2 Two Phases of Cancer Evolution
			1. Terminologies:
			2. The Dynamics of the Two Phases of Evolution
			3. Implications
		3.3.3 Genome Chaos: Reorganizing the Genomic Landscape
			1. What Happened?
			2. Causative Factors
			3. Mechanisms
			4. Implications
		3.3.4 The Evolutionary Mechanism of Cancer
			3.3.4.1 Linking Genome Heterogeneity to Tumorigenesis, Metastasis, and Drug Resistance
			3.3.4.2 Focus on the Evolutionary Mechanism of Cancer Rather Than the Diverse Individual Mechanisms
	3.4 A New Genomic Model for Cancer Evolution
		1. The Ultimate Cause of Cancer
		2. Cancer Evolution: The Game for Outliers
		3. Cancers Represent Emergent New Genome Systems
4 . Chromosomal Coding and Fuzzy Inheritance: The Genomic Basis of Bio-information and Heterogeneity
	4.1 Summary
	4.2 Chromosomal or Karyotype Coding
		4.2.1 The Rationale of Searching for New Types of Inheritance
		4.2.2 New Challenge: What Defines Inheritance?
		4.2.3 Genes Code “Parts Inheritance”
		4.2.4 A Chromosomal Set Codes “System Inheritance”
			4.2.4.1 Background and Rationale
			4.2.4.2 The Model and Its Prediction
			4.2.4.3 The Mechanism and Significance of Preserving Chromosomal Coding
		4.2.5 Why Has Chromosomal Coding Long Been Ignored (If It Is Indeed Important)?
			4.2.5.1 Historical Lessons: Topology Is a Key Piece of Bioinformation
			4.2.5.2 Accepting System Inheritance Is Necessary in the Search for the Correct Context of Genomic Information
			4.2.5.3 The Limitations of Reductionist Tradition and the Power of Metaphor
	4.3 Fuzzy Inheritance
		4.3.1 Rationales for Searching for New Types of Inheritance
		4.3.2 A New Inheritance Needs to Explain Heterogeneity: A Key Genomic Feature of Cellular Population
			1. Inheritance of a given unstable cellular population can pass the degree of genomic changes, but not specific changes
			2. System inheritance is unstable for many cell lines and can be drastically altered during crises
			3. A single cell can pass heterogeneity to an entire population
			4. Karyotype heterogeneity is associated with other cellular heterogeneities
			5. Inheritance of heterogeneity: the mechanism of heterogeneity
		4.3.3 The Inheritance of Heterogeneity in Organismal Systems in Both Physiological and Pathological Conditions
			1. Inheritance of heterogeneity can be universally observed in all types of organisms
			2. Abnormal phenotype and the hidden inheritance of heterogeneity from normal genomes
		4.3.4 The Definition of Fuzzy Inheritance and Its Key Differences Compared to Traditional Inheritance
		4.3.5 The Mechanisms of Fuzzy Inheritance
			a) Mechanisms of fuzzy inheritance at the karyotype level
			b) Mechanisms of fuzzy inheritance at CNV level
			c) Mechanisms of fuzzy inheritance at gene level
			d) Mechanisms of fuzzy inheritance at epigenetic level
			e) Mechanisms of fuzzy inheritance for mitochondrion
			f) Mechanisms of fuzzy inheritance of other interesting observations
		4.3.6 Potential Significance and Implications of Fuzzy Inheritance
	4.4 Overlooked Genome Variations
		4.4.1 Generally Accepted Chromosomal Variations
		4.4.2 Ignored and Unclassified Chromosomal/Nuclear Aberrations
			4.4.2.1 Free Chromatin
			4.4.2.2 Defective Mitotic Figures
			4.4.2.3 Chromosome Fragmentations
			4.4.2.4 Unit Fibers
			4.4.2.5 Sticky Chromosomes
			4.4.2.6 Genome Chaos
			4.4.2.7 Micronuclei Cluster
			4.4.2.8 Unclassified Chromosomal or Nuclear Abnormalities/Variations
			4.4.2.9 Unification of the Different Types of Chromosomal Aberrations
5 . Why Sex? Genome Reinterpretation Dethrones the Queen
	5.1 Summary
	5.2 What Is the Purpose of Sex? The Answer Is Not Obvious
	5.3 Surprise! Asexual Reproduction Does Not Generate Clonal Progenitors!
	5.4 The Search for the Main Function and Common Mechanism of Sex
	5.5 The Battle Is On: Changing Concepts
	5.6 Simulation: Ask the Simplest Question About the Function of Sex
	5.7 Case Studies: Reinterpretation Using New Framework
	5.8 Lessons Learned
		1. Focus on the first principle
		2. Follow the paradoxes
		3. Respect the facts
		4. Fill in knowledge gaps: Dare to think big
6 . Breaking the Genome Constraint: The Mechanism of Macroevolution
	6.1 Summary
	6.2 Pattern of Cellular Evolution Challenges Current Evolutionary Theory
		6.2.1 Simple Evolutionary Principles Are No Longer Simple
		6.2.2 Why the Cancer Model Is an Excellent Platform for Studying Evolution in General
		6.2.3 Similarities and Differences Between Somatic Cell Evolution and Natural Evolution
		6.2.4 The Conflict Between Observations From Somatic Cell Evolution and Neo-Darwinian Concepts
		6.2.5 Time to Compare/Reexamine Evolutionary Theories
	6.3 Artificial Selection and Natural Selection Are Fundamentally Different
	6.4 Both Isolated Cases and Isolated Natural Environments Represent Exceptions That Fail to Demonstrate the Relationship Betwee ...
	6.5 Maintaining Genome Integrity: The Major Evolutionary Constraint
		6.5.1 Why Are Evolutionary Constraints Important?
		6.5.2 Genome Integrity Represents the Major Evolutionary Constraint
			6.5.2.1 Why Is It Essential to Discuss Genome-Level Constraint?
				a. The genome codes for the package of an entire system.
				b. Sex safeguards genomic integrity.
				c. Sex-mediated genome integrity ensures long-term evolutionary stability.
				d. The genome—not the gene—is the macroevolutionary selection unit.
			6.5.2.2 Different Factors Contribute to Genome Constraint
	6.6 Implications of Genome Theory to Evolutionary Concepts
		6.6.1 The Concept of Species
		6.6.2 The Origin of Adaptation Differs From Speciation
		6.6.3 Genome Theory: Defining the Concept of Chromosome-Mediated Speciation
			1. Spontaneous chromosome alterations mediated speciation
			2. Hybrid speciation: chromosomes play an important role
			3. Genome chaos: massive speciation during crisis
			4. The core genome concept: limited fuzzy inheritance within populations
			5. Altered karyotypes and evolutionary certainty: understanding the genotype–phenotype relationship
			6. New species formation occurs much more frequently than suggested by natural selection, but the chance of the formation o ...
			7. What is the role of geographic isolation in speciation?
	6.7 Evolution Is True but Its Mechanism Must Be Reexamined
		6.7.1 The Integrated Model of Speciation: How Micro- and Macroevolution Create and Maintain Species
		6.7.2 Time for Reinterpretations
			a. Genome-based alternative mechanisms for evolution
			b. Fast or sluggish evolution?
			c. The irrelevance of the neutral theory
			d. The genome basis of punctuated equilibrium
			e. The invisible missing link in macroevolution
			f. Multilevel evolution and constraint
			g. Somatic cell dynamics and germline constraint
			h. Extinction issues
			i. The unified evolutionary theory?
	6.8 Implications: Creating Artificial Species by Shattering the Genome Followed by Artificial Mating/Genome Selection
		a. Creating new cell lines
		b. Creating artificial laboratory species
		c. Creating artificial animals/plants
7 . The Genome Theory: A New Framework
	7.1 Summary
	7.2 The Rationale for Establishing a Genome-Based Genomic Theory
	7.3 Unique Considerations for Genome Theory
		7.3.1 The Genome Is an Integrated Information Unit That Defines the Boundary of the System
		7.3.2 Emergent Properties in Biological Systems
		7.3.3 Understanding Genomic Principles Through the Lens of Evolution
	7.4 Outline of the Genome Theory
	7.5 The Predictions, Implications, Limitations, and Falsifiability of the Genome Theory
		7.5.1 Predictions
		7.5.2 Implications
		7.5.3 Limitations
		7.5.4 Falsifications
	7.6 Challenges Ahead
8 . The Rationale and Challenges of Molecular Medicine
	8.1 Summary
	8.2 A Brief History: The Promises of Molecular Medicine
	8.3 The Challenges and Opportunities for Precision Medicine
		8.3.1 The 40-Year Journey of Studying p53, From Certainty to Increased Uncertainty
		8.3.2 The Relationship Between Stress, Variation, Adaptation and Trade-Off, and Disease
		8.3.3 Genome Alterations and Common/Complex Diseases
			8.3.3.1 Key Features and Types of Common and Complex Diseases
			8.3.3.2 Stochastic Genomic Alterations Contribute to Most Common Diseases
			8.3.3.3 The Search for the General Model for Common and Complex Diseases/Illnesses: A Case Study for Gulf War Illness
			8.3.3.4 New Model With New Explanations
	8.4 Future Direction
		8.4.1 Facing Reality: The Increased Bio-Uncertainty
		8.4.2 Big Data, Artificial Intelligence, and Biomarkers for Adaptive Biosystems
			8.4.2.1 The Future of Big Data in Biological Systems
			8.4.2.2 Big Data Versus Theories: The End of Theories or the Beginning of Better Theories
			8.4.2.3 How to Collect the Necessary Data to Create a New Generation of Biomarkers?
			8.4.2.4 Big Data and Phenotypes
		8.4.3 Education and the Future of Biomedical Science
			8.4.3.1 Knowledge Structure
			8.4.3.2 Scientific Culture and Professionalism
			8.4.3.3 Policy Matters
Epilogue (or Why We Did What We Did)
Bibliography
Index
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