Efnisyfirlit

• Cover
• Half Title
• Title
• Copyright
• Contents
• Preface
• Acknowledgements
• 1 Fundamentals of DNA, Chromosomes, and Cells
  • 1.1 The Structure and Function of Nucleic Acids
    • General concepts: the genetic material, genomes, and genes
    • The underlying chemistry of nucleic acids
    • Base pairing and the double helix
    • DNA replication and DNA polymerases
    • Genes, transcription, and the central dogma of molecular biology
  • 1.2 The Structure and Function of Chromosomes
    • Why we need highly structured chromosomes, and how they are organized
    • Chromosome function: replication origins, centromeres, and telomeres
  • 1.3 DNA and Chromosomes in Cell Division and the Cell Cycle
    • Differences in DNA copy number between cells
    • The cell cycle and segregation of replicated chromosomes and DNA molecules
    • Mitosis: the usual form of cell division
    • Meiosis: a specialized reductive cell division giving rise to sperm and egg cells
    • Why each of our gametes is unique
  • Summary
  • Questions
  • Further Reading
• 2 Fundamentals of Gene Structure, Gene Expression, and Human Genome Organization
  • 2.1 Protein-Coding Genes: Structure and Expression
    • Gene organization: exons and introns
    • RNA splicing: stitching together the genetic information in exons
    • Translation: decoding messenger RNA to make a polypeptide
    • From newly synthesized polypeptide to mature protein
  • 2.2 RNA Genes and Noncoding RNA
    • The extraordinary secondary structure and versatility of RNA
    • RNAs that act as specific regulators: from quirky exceptions to the mainstream
  • 2.3 Working Out the Details of Our Genome and What They Mean
    • The Human Genome Project: working out the details of the nuclear genome
    • What the sequence didn’t tell us and the goal of identifying all functional human DNA sequences
  • 2.4 A Quick Tour of Some Electronic Resources Used to Interrogate the Human Genome Sequence and Gene Products
    • Gene nomenclature and the HGNC gateway
    • Databases storing nucleotide and protein sequences
    • Finding related nucleotide and protein sequences
    • Links to clinical databases
  • 2.5 The Organization and Evolution of the Human Genome
    • A brief overview of the evolutionary mechanisms that shaped our genome
    • How much of our genome is functionally significant?
    • The mitochondrial genome: economical usage but limited autonomy
    • Gene distribution in the human genome
    • The extent of repetitive DNA in the human genome
    • The organization of gene families
    • The significance of gene duplication and repetitive coding DNA
    • Highly repetitive noncoding DNA in the human genome
  • Summary
  • Questions
  • Further Reading
• 3 Principles Underlying Core DNA Technologies
  • 3.1 Amplifying DNA by DNA Cloning
    • Amplifying desired DNA within bacterial cells
    • The need for vector DNA molecules
    • Physical clone separation
    • The need for restriction nucleases
    • DNA libraries and the uses and limitations of DNA cloning
  • 3.2 Amplifying DNA Using the Polymerase Chain Reaction (PCR)
    • Basics of the polymerase chain reaction (PCR)
    • Quantitative PCR and real-time PCR
  • 3.3 Principles of Nucleic Acid Hybridization
    • Formation of artificial heteroduplexes
    • Hybridization assays: using known nucleic acids to find related sequences in a test nucleic acid population
    • Microarray hybridization: large-scale parallel hybridization to immobilized probes
  • 3.4 Principles of DNA Sequencing
    • Dideoxy DNA sequencing
    • Massively parallel DNA sequencing (next-generation sequencing)
  • Summary
  • Questions
  • Further Reading
• 4 Principles of Genetic Variation
  • 4.1 DNA Sequence Variation Origins and DNA Repair
    • Genetic variation arising from errors in chromosome and DNA function
    • Various endogenous and exogenous sources can cause damage to DNA by altering its chemical structure
    • The wide range of DNA repair mechanisms
    • Repair of DNA damage or altered sequence on a single DNA strand
    • Repair of DNA lesions that affect both DNA strands
    • Undetected DNA damage, DNA damage tolerance, and translesion synthesis
  • 4.2 Population Genomics and the Scale of Human Genetic Variation
    • DNA variants, polymorphisms, and human population genomics
    • Small-scale variation: single nucleotide variants and small insertions and deletions
    • Microsatellites and other variable number of tandem repeat (VNTR) polymorphisms
    • Structural variation and low copy number variation
    • Taking stock of human genetic variation
  • 4.3 Functional Genetic Variation and Protein Polymorphism
    • The vast majority of genetic variation has a neutral effect on the phenotype, but a small fraction is harmful
    • Different types of Darwinian natural selection operate in human lineages
    • Generating protein diversity by gene duplication: the example of olfactory receptor genes
  • 4.4 Extraordinary Genetic Variation in the Immune System
    • Pronounced genetic variation in four classes of immune system proteins
    • Programmed and random post-zygotic genetic variation
    • Somatic mechanisms allow cell-specific production of immunoglobulins and T-cell receptors
    • MHC (HLA) proteins: functions and polymorphism
    • The medical importance of the HLA system
  • Summary
  • Questions
  • Further Reading
• 5 Single-Gene Disorders: Inheritance Patterns, Phenotype Variability, and Allele Frequencies
  • 5.1 Introduction: Terminology, Electronic Resources, and Pedigrees
    • Background terminology and electronic resources with information on single-gene disorders
    • Investigating family history of disease and recording pedigrees
  • 5.2 The Basics of Mendelian and Mitochondrial DNA Inheritance Patterns
    • Autosomal dominant inheritance
    • Autosomal recessive inheritance
    • Sex-linked inheritance
    • Matrilineal inheritance for mitochondrial DNA disorders
  • 5.3 Uncertainty, Heterogeneity, and Variable Expression of Mendelian Phenotypes
    • Difficulties in defining the mode of inheritance in small pedigrees
    • Heterogeneity in the correspondence between phenotypes and the underlying genes and mutations
    • Nonpenetrance and age-related penetrance
  • 5.4 Allele Frequencies in Populations
    • Allele frequencies and the Hardy-Weinberg law
    • Applications and limitations of the Hardy-Weinberg law
    • Ways in which allele frequencies change in populations
    • Population bottlenecks and founder effects
    • Mutation versus selection in determining allele frequencies
    • Heterozygote advantage: when natural selection favors carriers of recessive disease
  • Summary
  • Questions
  • Further Reading
• 6 Principles of Gene Regulation and Epigenetics
  • The two fundamental types of gene regulation
  • Cis-acting and trans-acting effects in gene regulation
  • 6.1 Genetic Regulation of Gene Expression
    • Promoters: the major on–off switches in genes
    • Modulating transcription and tissue-specific regulation
    • Transcription factor binding and specificity
    • Genetic regulation during RNA processing: RNA splicing and RNA editing
    • Translational regulation by trans-acting regulatory proteins
    • Post-transcriptional gene silencing by microRNAs
    • Repressing the repressors: competing endogenous RNAs sequester miRNA
  • 6.2 Chromatin Modification and Epigenetic Factors in Gene Regulation
    • An overview of the molecular basis of epigenetic mechanisms
    • How changes in chromatin structure produce altered gene expression
    • Histone modification and histone substitution in nucleosomes
    • Modified histones and histone variants affect chromatin structure
    • The function of DNA methylation in mammalian cells
    • DNA methylation: mechanisms, heritability, and global roles during early development and gametogenesis
    • Long noncoding RNAs in mammalian epigenetic regulation
    • Genomic imprinting: differential expression of maternally and paternally inherited alleles
    • X-chromosome inactivation: compensating for sex differences in gene dosage
  • 6.3 Abnormal Epigenetic Regulation in Mendelian Disorders and Uniparental Disomy
    • Principles of epigenetic dysregulation
    • “Chromatin diseases” due to mutations in genes specifying chromatin modifiers
    • Disease resulting from dysregulation of heterochromatin
    • Uniparental disomy and disorders of imprinting
    • Abnormal gene regulation at imprinted loci
  • Summary
  • Questions
  • Further Reading
• 7 How Genetic Variation in DNA and Chromosomes Causes Disease
  • 7.1 An Overview of How Genetic Variation Results in Disease
    • The importance of repeat sequences in triggering pathogenesis
  • 7.2 Pathogenic Nucleotide Substitutions and Tiny Insertions and Deletions
    • Pathogenic single nucleotide substitutions within coding sequences
    • Mutations that result in premature termination codons
    • Genesis and frequency of pathogenic point mutations
    • Surveying and curating point mutations that cause disease
  • 7.3 Pathogenesis Due to Variation in Short Tandem Repeat Copy Number
    • The two main classes of pathogenic variation in short tandem repeat copy-number
    • Dynamic disease-causing mutations due to unstable expansion of short tandem repeats
    • Unstable expansion of short tandem repeats can cause disease in different ways
  • 7.4 Pathogenesis Triggered by Long Tandem Repeats and Interspersed Repeats
    • Pathogenic exchanges between repeats occurs in both nuclear DNA and mtDNA
    • Nonallelic homologous recombination and transposition
    • Pathogenic sequence exchanges between chromatids at mispaired tandem repeats
    • Disease arising from sequence exchanges between distantly located repeats in nuclear DNA
  • 7.5 Chromosome Abnormalities
    • Structural chromosomal abnormalities
    • Chromosomal abnormalities involving gain or loss of complete chromosomes
  • 7.6 Molecular Pathology of Mitochondrial Disorders
    • Mitochondrial disorders due to mtDNA mutation show maternal inheritance and variable proportions of mutant genotypes
    • The two major classes of pathogenic DNA variant in mtDNA: large deletions and point mutations
  • 7.7 Effects on the Phenotype of Pathogenic Variants in Nuclear DNA
    • Mutations affecting how a single gene works: an overview of loss of function and gain of function
    • The effect of pathogenic variants depends on how the products of alleles interact: dominance and recessiveness revisited
    • Gain-of-function and loss-of-function mutations in the same gene can produce different phenotypes
    • Multiple gene dysregulation resulting from aneuploidies and mutations in regulatory genes
  • 7.8 A Protein Structure Perspective of Molecular Pathology
    • Pathogenesis arising from protein misfolding
    • The many different ways in which protein aggregation can result in disease
  • 7.9 Genotype–Phenotype Correlations and Why Monogenic Disorders are Often Not Simple
    • The difficulty in getting reliable genotype–phenotype correlations
    • Modifier genes and environmental factors: common explanations for poor genotype–phenotype correlations
  • Summary
  • Questions
  • Further Reading
• 8 Identifying Disease Genes and Genetic Susceptibility to Complex Disease
  • 8.1 Identifying Genes in Monogenic Disorders
    • A historical overview of identifying genes in monogenic disorders
    • Linkage analysis to map genes for monogenic disorders to defined subchromosomal regions
    • Chromosome abnormalities and other large-scale mutations as routes to identifying disease genes
    • Exome sequencing: let’s not bother getting a position for disease genes!
  • 8.2 Approaches to Mapping and Identifying Genetic Susceptibility to Complex Disease
    • The polygenic and multifactorial nature of common genetic disorders
    • Difficulties with lack of penetrance and phenotype classification in complex disease
    • Estimating heritability: the contribution made by genetic factors to the variance of complex diseases
    • The very limited success of linkage analyses in identifying genes underlying complex genetic diseases
    • The fundamentals of allelic association and the importance of HLA-disease associations
    • Linkage disequilibrium as the basis of allelic associations
    • How genomewide association studies are carried out
    • Moving from candidate subchromosomal region to identify causal genetic variants in complex disease can be challenging
    • The limitations of GWA studies and the issue of missing heritability
    • Alternative genome-wide studies and the role of rare variants and copy number variants in complex disease
    • The assessment and prediction of risk for common genetic diseases and the development of polygenic risk scores
  • 8.3 Aspects of the Genetic Architecture of Complex Disease and the Contributions of Environmental and Epigenetic Factors
    • Common neurodegenerative disease: from monogenic to polygenic disease
    • The importance of immune system pathways in common genetic disease
    • The importance of protective factors and how a susceptibility factor for one complex disease may be a protective factor for another disease
    • Gene–environment interactions in complex disease
    • Epigenetics in complex disease and aging: significance and experimental approaches
  • Summary
  • Questions
  • Further Reading
• 9 Genetic Approaches to Treating Disease
  • 9.1 An Overview of Treating Genetic Disease and of Genetic Treatment of Disease
    • Three different broad approaches to treating genetic disorders
    • Very different treatment options for different inborn errors of metabolism
    • Genetic treatment of disease may be conducted at many different levels
  • 9.2 Genetic Inputs into Treating Disease with Small Molecule Drugs and Therapeutic Proteins
    • An overview of how genetic differences affect the metabolism and performance of small molecule drugs
    • Phenotype differences arising from genetic variation in drug metabolism
    • Genetic variation in enzymes that work in phase II drug metabolism
    • Altered drug responses resulting from genetic variation in drug targets
    • When genotypes at multiple loci in patients are important in drug treatment: the example of warfarin
    • Translating genetic advances: from identifying novel disease genes to therapeutic small molecule drugs
    • Translating genomic advances and developing generic drugs as a way of overcoming the problem of too few drug targets
    • Developing biological drugs: therapeutic proteins produced by genetic engineering
    • Genetically engineered therapeutic antibodies with improved therapeutic potential
  • 9.3 Principles of Gene and Cell Therapy
    • Two broad strategies in somatic gene therapy
    • The delivery problem: designing optimal and safe strategies for getting genetic constructs into the cells of patients
    • Different ways of delivering therapeutic genetic constructs, and the advantages of ex vivo gene therapy
    • Viral delivery of therapeutic gene constructs: relatively high efficiency but safety concerns
    • Virus vectors used in gene therapy
    • The importance of disease models for testing potential therapies in humans
  • 9.4 Gene Therapy for Inherited Disorders: Practice and Future Directions
    • Multiple successes for ex vivo gene supplementation therapy targeted at hematopoietic stem cells
    • In vivo gene therapy: approaches, barriers, and recent successes
    • An overview of RNA and oligonucleotide therapeutics
    • RNA interference therapy
    • Future therapeutic prospects using CRISPR-Cas gene editing
    • Therapeutic applications of stem cells and cell reprogramming
    • Obstacles to overcome in cell therapy
    • A special case: preventing transmission of severe mitochondrial DNA disorders by mitochondrial replacement
  • Summary
  • Questions
  • Further Reading
• 10 Cancer Genetics and Genomics
  • 10.1 Fundamental Characteristics and Evolution of Cancer
    • The defining features of unregulated cell growth and cancer
    • Why cancers are different from other diseases: the contest between natural selection operating at the level of the cell and the level of the organism
    • Cancer cells acquire several distinguishing biological characteristics during their evolution
    • The initiation and multistage nature of cancer evolution and why most human cancers develop over many decades
    • Intratumor heterogeneity arises through cell infiltration, clonal evolution, and differentiation of cancer stem cells
  • 10.2 Oncogenes and Tumor Suppressor Genes
    • Two fundamental classes of cancer gene
    • Viral oncogenes and the natural roles of cellular oncogenes
    • How normal cellular proto-oncogenes are activated to become cancer genes
    • Tumor suppressor genes: normal functions, the two-hit paradigm, and loss of heterozygosity in linked markers
    • The key roles of gatekeeper tumor suppressor genes in suppressing G1-S transition in the cell cycle
    • The additional role of p53 in activating different apoptosis pathways to ensure that rogue cells are destroyed
    • Tumor suppressor involvement in rare familial cancers and non-classical tumor suppressors
    • The significance of miRNAs and long noncoding RNAs in cancer
  • 10.3 Genomic Instability and Epigenetic Dysregulation in Cancer
    • Different types of chromosomal instability in cancer
    • Deficiency in mismatch repair results in unrepaired replication errors and global DNA instability
    • Different classes of cancer susceptibility gene according to epigenetic function, epigenetic dysregulation, and epigenome–genome interaction
  • 10.4 New Insights from Genome-Wide Studies of Cancers
    • Genome sequencing has revealed extraordinary mutational diversity in tumors and insights into cancer evolution
    • Defining the landscape of driver mutations in cancer and establishing a complete inventory of cancer-susceptibility genes
    • Tracing the mutational history of cancers: just one of the diverse applications of single-cell genomics and transcriptomics in cancer
    • Genome-wide RNA sequencing enables insights into the link between cancer genomes and cancer biology and aids tumor classification
  • 10.5 Genetic Inroads into Cancer Therapy
    • Targeted anticancer therapies are directed against key cancer cell proteins involved in oncogenesis or in escaping immunosurveillance
    • CAR-T Cell therapy and the use of genetically engineered T cells to treat cancer
    • The molecular basis of tumor recurrence and the evolution of drug resistance in cancers
    • The promise of combinatorial drug therapies
  • Summary
  • Questions
  • Further Reading
• 11 Genetic and Genomic Testing in Healthcare: Practical and Ethical Aspects
  • 11.1 An Overview of Genetic Testing
    • The different source materials and different levels of genetic testing
  • 11.2 Genetic Testing for Chromosome Abnormalities and Pathogenic Structural Variation
    • Screening for aneuploidies using quantitative fluorescence PCR
    • Detecting large-scale copy number variants using chromosome SNP microarray analysis
    • Detecting and scanning for oncogenic fusion genes using, respectively, chromosome FISH and targeted RNA sequencing
    • Detecting pathogenic moderate- to small-scale deletions and duplications at defined loci is often achieved using the MLPA or ddPCR methods
    • Two very different routes towards universal genome-wide screens for structural variation: genome-wide sequencing and optical genome mapping
  • 11.3 Genetic and Genomic Testing for Pathogenic Point Mutations and DNA Methylation Testing
    • Diverse methods permit rapid genotyping of specific point mutations
    • The advantages of multiplex genotyping
    • Mutation scanning: from genes and gene panels to whole exome and whole genome sequencing
    • Interpreting and validating sequence variants can be aided by extensive online resources
    • Detecting aberrant DNA methylation profiles associated with disease
  • 11.4 Genetic and Genomic Testing: Organization of Services and Practical Applications
    • The developing transformation of genetic services into mainstream genomic medicine
    • An overview of diagnostic and pre-symptomatic or predictive genetic testing
    • The different ways in which diagnosis of genetic conditions is carried out in the prenatal period
    • Preimplantation genetic testing is carried out to prevent the transmission of a harmful genetic defect using in vitro fertilization
    • Noninvasive prenatal testing (NIPT) and whole genome testing of the fetus
    • An overview of the different types of genetic screening
    • Pregnancy screening for fetal abnormalities
    • Newborn screening allows the possibility of early medical intervention
    • Different types of carrier screening can be carried out for autosomal recessive conditions
    • New genomic technologies are being exploited in cancer diagnostics
    • Bypassing healthcare services: the rise of direct-to-consumer (DTC) genetic testing
    • The downsides of improved sensitivity through whole genome sequencing: increased uncertainty about what variants mean
  • 11.5 Ethical, Legal, and Societal Issues (ELSI) in Genetic Testing
    • Genetic information as family information
    • Consent issues in genetic testing
    • The generation of genetic data is outstripping the ability to provide clinical interpretation
    • New disease gene discovery and changing concepts of diagnosis
    • Complications in diagnosing mitochondrial disease
    • Complications arising from incidental, additional, secondary, or unexpected information
    • Consent issues in testing children
    • Ethical and societal issues in prenatal diagnosis and testing
    • Ethical and social issues in some emerging treatments for genetic disorders
    • The ethics of germline gene modification for gene therapy and genetic enhancement
  • Summary
  • Questions
  • Further Reading
• Glossary
• Index

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