Single Nucleotide Polymorphisms: Human Variation and a Coming Revolution in Biology and Medicine

Introduction and Overview: Single Nucleotide Polymorphisms, Human Variation, and a Coming Revolution in Biology and Medicine
Introduction
Overview of the Book
Part I: An Overview of Human Genome Sequencing and How to Access Information About SNVs
Part II: A Broad Survey of SNPs, Their Classification into Synonymous and Non-synonymous, and the Undesirable Consequences of Using the Term “Silent” for Synonymous Changes
Part III: The Role of SNPs in Human Diseases
Part IV: An Examination of the Mechanisms by Which Synonymous Mutations Affect Protein Levels or Protein Folding, Which Affect Human Physiology and Response to Therapy
Part V: The Role of SNPs in Personalized Medicine and the Platform Technology of Codon Optimization
Summary
References
Contents
Part I: An Overview of Human Genome Sequencing and How to Access Information About SNVs
Chapter 1: SNPs Classification and Terminology: dbSNP Reference SNP (rs) Gene and Consequence Annotation
1.1 Introduction
1.2 What Is dbSNP Used for?
1.3 dbSNP Molecular Consequences (AKA Function Class)
1.4 Computed Molecular vs. Observed Functional Consequences
1.5 Computing Molecular Consequences in dbSNP
1.6 Splicing Variants
1.7 Other Non-CDS Variants
1.8 Searching dbSNP by Variant Consequences
References
Part II: A Broad Survey of SNPs, Their Classification into Synonymous and Non-synonymous and the Undesirable Consequences of Using the Term “Silent” for Synonymous Changes
Chapter 2: Evolutionary Forces That Generate SNPs: The Evolutionary Impacts of Synonymous Mutations
2.1 Introduction
2.2 Evidence for the Evolutionary Impacts of Synonymous Mutations
2.2.1 Indirect Evidence
2.2.2 Direct Evidence
2.3 Changing Evolutionary Perspectives on Synonymous Mutations
2.3.1 Phase I: Mostly Neutral
2.3.2 Phase II: Weak Translational Selection
2.3.3 Phase III: Pervasive (Sometimes Strong) Selection, Diverse Mechanisms
2.4 Summary and Future Directions
2.4.1 Building a Cohesive Evolutionary Framework
2.4.2 Predicting the Evolutionary Fate of Synonymous Mutations
2.4.3 Developing New Methods to Identify Signatures of Selection
2.4.4 Determining the Evolutionary History of Mechanisms Driving Selection at Synonymous Sites
References
Chapter 3: Recording Silence – Accurate Annotation of the Genetic Sequence Is Required to Better Understand How Synonymous Coding Affects Protein Structure and Disease
3.1 Synonymous But Not Silent
3.2 An Ironic Oversight in Structural Biology
3.3 Lost Opportunities in the Machine Learning Revolution
3.4 Silently Shaping the Edifice of Life
References
Part III: The Role of SNPs in Human Disease
Chapter 4: GWAS to Identify SNPs Associated with Common Diseases and Individual Risk: Genome Wide Association Studies (GWAS) to Identify SNPs Associated with Common Diseases and Individual Risk
4.1 Introduction
4.2 Fundamental Concepts of GWAS
4.2.1 SNPs and Linkage Disequilibrium
4.2.2 GWAS Data Interpretation
4.2.2.1 Association Model: Determining Genotype – Phenotype Associations
4.2.2.2 Classifier Model: Disease Risk Prediction
4.3 GWAS Applications and Impact
4.3.1 Expanding the Scientific Landscape: Elucidating the Origins and Mechanisms of Disease Manifestation
4.3.2 Elevating Patient Care: Identifying Novel Therapeutic Targets, Improving Individual Risk Assessment and Harnessing Personalized Medicine
4.3.3 Commercial: Direct-to-Consumer Personal Genotyping
4.4 GWAS Limitations and Controversy
4.4.1 Missing Heritability
4.4.2 Other Limiting Factors
4.5 Discovering True SNP-Associations: Factors to Consider
4.5.1 Population Sampling
4.5.2 Technology
4.5.3 Data Quality
4.5.4 Data Analysis
4.5.5 Data Validation
4.5.6 Data Meta-Analysis
4.5.7 Follow-Up Analysis of Confirmed Signals
4.6 Concluding Remarks
4.7 Notes
References
Untitled
Chapter 5: SNPs Ability to Influence Disease Risk: Breaking the Silence on Synonymous Mutations in Cancer
5.1 Introduction
5.2 Why Synonymous Mutations Have Remained Silent for a Long Time in the Cancer Field
5.3 Screenings for Synonymous Cancer Driver Mutations
5.4 How Synonymous Mutations Break the Silence
5.4.1 Splicing
5.4.2 mRNA Structure
5.4.3 Codon Usage
5.4.4 Protein Stability
5.4.5 Other Mechanisms
5.5 What Is Needed to Entirely Break the Silence on Synonymous Mutations?
References
Part IV: An Examination of the Mechanisms by Which Synonymous Mutations Affect Protein Levels or Protein Folding Which Affect Human Physiology and Response to Therapy
Chapter 6: An Examination of Mechanisms by which Synonymous Mutations may Alter Protein Levels, Structure and Functions
6.1 Introduction
6.2 Proposed Mechanisms by Which Synonymous Mutations Alter Translation and Protein Folding
6.2.1 Synonymous Mutations Affecting Pre-mRNA Processing
6.2.1.1 Examples of sSNP-Associated Pre-mRNA Processing Defects
6.2.2 Altered Binding of Micro-RNAs Targeting Protein-Coding Regions (ORFs)
6.2.2.1 Examples of Human Disorders with sSNPs Altering Coding Sequence Targets of miRNAs
6.2.3 Codon Optimality and tRNA Abundance
6.2.3.1 Switch from a Frequent to a Rare Codon with Low tRNA Abundance
6.2.3.2 Switch from a High to Very Low Abundance tRNA Decoder
6.2.3.3 Switch from a Rare to a More Frequent Codon with High tRNA Abundance
6.2.4 Codon Optimality, Synonymous Codon Usage, and mRNA Half-Life
6.2.4.1 Synonymous Mutation Resulting in Reduced mRNA Stability
6.2.5 Synonymous Mutations Altering mRNA Secondary Structures Without Changing mRNA Half-Life
6.2.6 Predicting the Consequences of Synonymous Mutations
6.2.6.1 In Silico Analysis of sSNPs in CFTR
6.2.7 Multiple Synonymous Mutations and Their Consequences.
6.3 Prospective
References
Chapter 7: Methods to Evaluate the Effects of Synonymous Variants
7.1 Introduction
7.2 Exploring the Effects of Synonymous Variants on mRNA
7.2.1 Fitness, Codon Usage Bias, and mRNA Transcription
7.2.2 Evaluation of mRNA Structure and Stability
7.2.3 Study of Pre-mRNA Splicing
7.2.4 Detecting Changes in miRNA Binding
7.3 Exploring the Effects of Synonymous Variants on Proteins
7.3.1 Monitoring Translation Kinetics
7.3.2 Analysis of Subtle Structural Changes
7.3.3 Assessment of Stability Changes
7.3.4 Evaluation of Immunogenicity Risk
7.4 In-Silico Tools for Predicting Comprehensive Effects of Synonymous Variants
References
Part V: The Role of SNPs in Personalized Medicine and the Platform Technology of Codon Optimization
Chapter 8: Using Genome Wide Studies to Generate and Test Hypotheses that Provide Mechanistic Details of How Synonymous Codons Affect Protein Structure and Function: Functional SNPs in the Age of Precision Medicine
8.1 Genetics in Precision Medicine
8.2 Functional Role of Coding and Non-coding SNPs
8.3 Future Directions and Challenges
References
Chapter 9: SNPs and Personalized Medicine: Scrutinizing Pathogenic Synonymous Mutations for Precision Oncology
9.1 Introduction
9.2 Biomarkers and Next-Generation Sequencing for Personalized Medicine
9.3 The Impact of Pathogenic Synonymous Mutations in Prognosis and Precision Medicine
9.4 Algorithms for Predicting Pathogenic Synonymous Mutations
9.5 Concluding Remarks and Future Perspectives
References
Chapter 10: Condon Optimization: Codon Optimization of Therapeutic Proteins: Suggested Criteria for Increased Efficacy and Safety
10.1 Introduction
10.2 Protein Synthesis Primer
10.2.1 Translation Initiation
10.2.2 Polypeptide Synthesis
10.3 Codon Optimization
10.3.1 Codon Usage and Other Features of mRNA That Affect Protein Expression
10.3.2 Codon Optimization Approaches
10.3.3 Widespread Acceptance of Codon Optimization
10.4 Potential Problems with Codon Optimization for Therapeutics
10.4.1 Overlapping Information
10.4.2 Questionable Assumptions in Higher Eukaryotes
10.4.3 Disruption of Protein Conformation
10.4.4 Immunogenicity
10.5 Potential Benefits of Codon Optimization
10.6 Potential Risks of Codon Optimization for Gene Therapy and mRNA Therapeutics
10.7 Alternative Technologies for Increased Protein Production
10.8 Recommendations for Therapeutic Applications
References
Index