Human Genome Structure, Function and Clinical Considerations

Preface
Contents
Chapter 1: An Overview of the Human Genome
	1.1 General Introduction
	1.2 A Bird’s-Eye View of Selected Aspects of the Structure and Evolution of the Human Genome
		1.2.1 Introduction
		1.2.2 The Basic Morphological Division of the Human Genome: Chromosomes
		1.2.3 Coding DNA and Non-coding DNA
		1.2.4 Natural Selection and Genome Evolution
		1.2.5 A Borgesian View of the Human Genome
	1.3 Consequence of the Abundance of Retroposons, Retrotransposons and Endogenous Retrovirus in the Human Genome
	1.4 Genomic Sequencing as a Clinical Tool for the Accurate Prediction of Disease Risk in Precision Medicine
		1.4.1 What Is Precision Medicine?
		1.4.2 New-Generation DNA Sequencing (NGS)
		1.4.3 Pathogenic Mendelian Variants (“Monogenic”)
		1.4.4 Cumulative Effect of Numerous Common Variants (“Polygenic”)
	References
Chapter 2: Human Chromosomes
	2.1 Introduction
	2.2 DNA Replication
	2.3 Chromatin
	2.4 Chromosomes
	2.5 Number and Morphology of Human Chromosomes
	2.6 The Normal Karyotype
		2.6.1 Autosomal Chromosomes
		2.6.2 Sex Chromosomes
	2.7 Chromosomes and Cell Division
	2.8 Chromosome Abnormalities
		2.8.1 Numerical Chromosome Abnormalities
			2.8.1.1 Numerical Chromosomopaties
				Monosomy X
				Trisomy 21
				Trisomy 18
				Trisomy 13
				Trisomy of Sex Chromosomes
			2.8.1.2 Poliploydy and Molar Pregnancies
		2.8.2 Structural Chromosome Abnormalities
			2.8.2.1 Deletion
			2.8.2.2 Duplication
			2.8.2.3 Translocation
			2.8.2.4 Reciprocal Translocations
			2.8.2.5 Robertsonian Translocations
			2.8.2.6 Isochromosomes
			2.8.2.7 Inversions
	2.9 Some Considerations about Chromosome Abnormalities
	2.10 Genomic Disorders
	2.11 Methods for the Study of Chromosomes
		2.11.1 Karyotype
		2.11.2 FISH Test
		2.11.3 Chromosome Microarray
		2.11.4 Whole-Genome Sequencing
	2.12 Cytogenomic Nomenclature
	2.13 Final Remarks
	References
Chapter 3: Methods to Study Genomic DNA Sequence Variation
	3.1 Introduction
	3.2 Variant Categories
	3.3 Methods in Genomic Analyses
		3.3.1 Fragment-Based Methods
			3.3.1.1 Fluorescence In-Situ Hybridization (FISH)
			3.3.1.2 Array Comparative Genomic Hybridization (Array-CGH or aCGH)
			3.3.1.3 Multiplex Ligation-Dependent Probe Amplification (MLPA)
			3.3.1.4 Triplet Repeat Primed PCR (TP-PCR)
		3.3.2 Sequence-Based Methods
			3.3.2.1 Sanger Sequencing
			3.3.2.2 Genotyping Microarrays
			3.3.2.3 Next-Generation Sequencing
	3.4 Analysis of Rare and Common Variants to Understand Diseases and Traits
		3.4.1 Workflow for Molecular Diagnosis
		3.4.2 Rare-Variant Association Testing
		3.4.3 Polygenic Risk Scores
	3.5 Perspectives
		3.5.1 Cell-Free DNA
		3.5.2 Long-Read Sequencing
		3.5.3 Omics Integration
	References
Chapter 4: Protein-Coding Genes
	4.1 Introduction
	4.2 Linear and Structural Elements Controlling Transcription and Primary Transcript Processing
		4.2.1 Gene Transcription-Regulating cis Elements
			4.2.1.1 The POLII Promoter
			4.2.1.2 Transcription Regulatory Elements
		4.2.2 Chromatin Remodeling
			4.2.2.1 Cytosine Methylation
			4.2.2.2 Histone isoforms and Post-Translational Modifications
			4.2.2.3 Insulators, Locus Control Regions and Enhancer Blocking
		4.2.3 The TP53 Gene: A Genetic Case Study on Promoters and Enhancers
			4.2.3.1 Trans-Acting p53 effects on Gene Transcription
			4.2.3.2 TP53 Gene Transcription
			4.2.3.3 Germline and Somatic TP53 Pathogenic DNA Variants
		4.2.4 Gene Elements Driving the Primary Transcript Processing
			4.2.4.1 Exons
			4.2.4.2 Introns and Splicing
			4.2.4.3 The SMN1 and SMN2 Genes: A Genetic Case Study on Splicing
			4.2.4.4 Polyadenylation Signal: A cis Element on Transcript’s Last Exon
		4.2.5 The ENCODE Project
	4.3 Protein-Coding Gene Families
		4.3.1 Pseudogenes
		4.3.2 Protein Domains as Evolutionary Modules
		4.3.3 Developmental Expression of the Human Beta-Globin Locus Genes
	4.4 DNA Variants May Occur de novo or Be Inherited
	4.5 Genomic imprinting and Non-classic Mendelian Inheritance
	4.6 Final Remarks: The Evolving Concept of Protein-Coding Genes
	References
Chapter 5: Noncoding Gene Families of the Human Genome
	5.1 Noncoding Genes: Finding Treasure in Junk
	5.2 RNA: A Versatile Molecule
	5.3 Noncoding Gene Families
		5.3.1 Housekeeping ncRNAs
		5.3.2 Small Noncoding RNAs
		5.3.3 Long Noncoding RNAs
	5.4 Clinical Relevance of ncRNAs
	5.5 Challenges and Open Questions in the Noncoding RNA Field
	References
Chapter 6: Satellite and Tandem DNA Repeats in the Human Genome
	6.1 Introduction
	6.2 Satellite DNA
	6.3 Tandem DNA Repeats
		6.3.1 Microsatellite DNA (STR)
	6.4 Dynamic Mutations: Expansion of Transcribed, Unstable Tandem Repeats
		6.4.1 5′UTR CGG/GCC Repeats and Rare Chromosomal Fragile Sites
			6.4.1.1 One Family, Three Generations, Three Distinct Clinical Conditions
			6.4.1.2 Genetic Pathophysiology of FMR1 Premutation
		6.4.2 3′UTR CTG repeats and Type 1 Myotonic Dystrophy
		6.4.3 Translated CAG Repeats
		6.4.4 Expansion of Intronic Tri-, Tetra-, Penta- and Hexanucleotide Repeats
	6.5 Final Remarks
	References
Chapter 7: Human Chromosome Telomeres
	7.1 Introduction
	7.2 History
	7.3 Human Telomeres: Maintenance for Genome Stability and Cell Proliferation
		7.3.1 Telomeres and Their Structural Features
		7.3.2 The Importance of Telomeres’ Replication for Genome Stability and Integrity
			7.3.2.1 The Telomerase Ribonucleoprotein Complex
			7.3.2.2 Elongation of Telomeres by Telomerase
			7.3.2.3 Alternative Lengthening of Telomeres
		7.3.3 Telomere Length Regulation
			7.3.3.1 The Intercrossed Actions Between Shelterin and the CST Complex
			7.3.3.2 Telomere Transcription and the Importance of Terra in Telomere Maintenance
	7.4 Telomeres and Biological Age
		7.4.1 Environmental Determinants of Telomere Shortening
		7.4.2 Intrinsic Factors for Telomere Shortening
	7.5 Telomere Dysfunction in Human Diseases
	7.6 Telomeres as Targets for Disease Management
		7.6.1 Telomerase Inhibition in Cancer
		7.6.2 Senescent Cells and Senolytic Drugs
	7.7 Conclusions and Future Directions
	References
Chapter 8: To Build or To Break: The Dual Impact of Interspersed Transposable Elements in Cancer
	8.1 Transposable Elements Diversity
	8.2 Transposable Elements’ Regulation
	8.3 Beneficial Impacts of Transposable Elements
	8.4 Deleterious Impacts of Transposable Elements
	8.5 Transposable Elements and Cancer
	8.6 Transposable Elements Activation and Cancer Treatment
	8.7 The Use of Transposable Elements as Tools in Precision Medicine
	8.8 Concluding Remarks
	Bibliography
Chapter 9: Copy Number Variation in the Human Genome
	9.1 Copy Number Variation: A Brief Description and Overview of its Impacts and Mechanisms of Origin
	9.2 CNVs Are Major Contributors to Phenotypic Variation in the Human Genome
	9.3 Analysis of Copy Number Variants
		9.3.1 G-Band Karyotyping
		9.3.2 Fluorescence In Situ Hybridization (FISH)
		9.3.3 Multiplex Ligation-Dependent Probe Analysis (MLPA)
		9.3.4 Polymerase Chain Reaction (PCR)
		9.3.5 Hybridization-Based Microarray Approaches
		9.3.6 Next-Generation Sequencing (NGS)
	9.4 CNVs and Human Diseases
		9.4.1 CNVs and Neurological Diseases: The PMP22 Gene as an Example
		9.4.2 CNVs and Cancer
		9.4.3 CNVs and Malformative Syndromes
		9.4.4 CNVs and Neurodevelopmental Disorders
	9.5 Clinical Application of CNV Study in Human Disease
		9.5.1 Clinical Case 1
		9.5.2 Clinical Case 2
		9.5.3 Clinical Case 3
	9.6 Closing Remarks
	References
Chapter 10: The Human Mitochondrial DNA
	10.1 The Origin and the Structure of the Human Mitochondrial DNA (mtDNA)
	10.2 The Mutation Rates in mtDNA are Elevated When Compared to Nuclear DNA
	10.3 Rare mtDNA Variants Lead to Hereditary Diseases with Maternal Transmission
	10.4 Heteroplasmy Is a Generalized Phenomenon in mtDNA Inheritance and Relates to the Clinical Expression of Diseases
	10.5 Human mtDNA Is Maternally Transmitted, But Striking Exceptions Have Been Described
	10.6 Frequent mtDNA Variants Define Haplogroups Correlated to the Geographical Patterns of Dispersion of Modern Humans
	10.7 Frequent mtDNA Variants Correlate with Increased Susceptibility to Complex Disorders
	10.8 Somatic Variation Accumulated in the mtDNA is Related to Aging and Diseases
	10.9 mtDNA Disorders
	10.10 mtDNA is Related to Inflammation and Immunity
	10.11 mtDNA and Epigenetics
	References
Chapter 11: Population Variation of the Human Genome
	11.1 What Is Genomic Variation?
	11.2 An Evolutionary Perspective on Human Diversity
	11.3 Archaic Hominin Introgression as an Unexpected Source of Variation
	11.4 The Origin and Diversity of Indigenous Populations in Pre-Columbian Times
	11.5 Genomic Variation of Contemporaneous Human Societies
	11.6 Variation in Simple and Complex Phenotypes and Inherited Diseases
	11.7 Variation and Rare Genetic Diseases
	11.8 Human Variation in the Prognosis of Pathogenic Diseases
	11.9 Human Variation in the Immune Response
	11.10 Epigenetic Variation
	References
Index