Introduction to Genomics
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Our genome is the blueprint for our existence: it encodes all the information we need to develop from a single cell into a hugely complicated functional organism. Yet it is more than a static information store: our genome is a dynamic, tightly regulated collection of genes, which switch on and off in many combinations to give the variety of cells from which our bodies are formed. But how do we identify the genes that make up our genome? How do we determine their function? And how do different genes form the regulatory networks that direct the processes of life? Introduction to Genomics is the most up-to-date and complete textbook for students approaching the subject for the first time.
Lesk's engaging writing style brings a narrative to a disparate field of study and offers a fascinating insight into what can be revealed from the study of genomes. The book covers: the similarities and differences between organisms; how different organisms evolved; how the genome is constructed and how it operates; and what our understanding of genomics means in terms of our future health and wellbeing.
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- Oxford University Press Academic UK
- 9780192636706
- 9780198866893
- ePub
- 4
- Arthur Lesk
- English
- 2025-04-28
- 100
- 2
- 2
Kaflar
- Cover Page
- Title page
- Copyright page
- Dedication
- Preface
- Plan of the Fourth Edition
- Additional Reading
- Acknowledgements
- Table of Contents
- List of Abbreviations
- Chapter 1 Introduction and Background
- Genomics: the hub of biology
- What’s in a genome?
- Phenotype ← genotype + environment + life history + epigenetics
- Varieties of genome organization
- Chromosomes, organelles, and plasmids
- The scope and applications of genome sequencing projects
- Comparisons of genome sequences
- Mutations and disease
- By what mechanisms can mutations affect human health?
- Haplotypes
- A clinically important haplotype: the major histocompatibility complex
- Genome projects and our current library of genome information
- High-throughput sequencing
- De novo sequencing
- Resequencing
- Human genome sequencing
- Human genomes and medicine
- Prevention of disease
- Detection and precise diagnosis
- Genetic counselling—carrier status
- Discovery and implementation of effective treatment
- Health care delivery
- Genes
- Protein evolution: divergence of sequences and structures within and between species
- Mechanisms of protein evolution
- Species
- Populations
- The biosphere
- Extinctions
- Extinction of the thylacine (Thylacinus cynocephalus)
- Survival of Père David’s deer (Elaphurus davidianus)
- Is extinction reversible?
- The future?
- CRISPRs (clustered regularly interspaced short palindromic repeats) and their applications to genetic engineering
- Gene drive
- Dynamic components of genomes
- Genomics and developmental biology
- Genes and minds: neurogenomics
- Genetics of behaviour
- Proteomics
- Organization and regulation
- Some mechanisms of regulation act at the level of transcription
- Some mechanisms of regulation act at the level of translation
- Some regulatory mechanisms affect protein activity
- Summary
- Recommended Reading
- The first three items are books that are sources for the history of the development of molecular biology after the Second World War. Rosenfield, Ziff, & Van Loon’s is a less formal but not less serious account of the founding people and events.
- The next publications deal with genomics and the Human Genome Project, placing it in broad context. These are selections from a very large literature.
- Sequencing projects for other species
- Pharmacogenomics
- Extinctions
- Genomics and neurobiology
- Genetic modification using the CRISPR/Cas system
- Genome informatics: a selection of articles and books
- Publications dealing with ethical, legal, and social aspects of genomics and its applications
- Companion volumes to this one
- Exercises, Problems, and Weblems
- Exercises
- Problems
- Weblems
- List of Key Terms
- Chapter 2 The Human Genome Project: Achievements and Applications
- ‘… the end of the beginning’
- Human genome sequencing
- Large-scale sequencing projects
- What makes us human?
- Comparative genomics
- Genomics and language
- ‘Pop’ applications of genome sequencing
- Genomics in personal identification
- DNA ‘fingerprinting’
- Personal identification by amplification of specific regions has superseded the RFLP approach
- Mitochondrial DNA
- Identification of non-human DNA sequences
- Parentage testing
- Reverse paternity testing
- Inference of physical features, and even family name
- Solutions of ‘cold cases’
- Ethical, legal, and social issues
- Databases containing human DNA sequence information
- Use of DNA sequencing in research on human subjects
- Recommended Reading
- Personal accounts by two of the major players
- A useful short summary, although, like anything else in print, somewhat out of date
- The general consequences of mutation
- Identification of remains of Russian royal family
- Interactions, and collisions, between scientific advances and social policy; including, but not limited to, issues of privacy
- Exercises, Problems, and Weblems
- Exercises
- Problems
- Weblems
- List of Key Terms
- Chapter 3 Bioinformatics
- Databases in molecular biology
- Observables and data archives
- Annotation
- Database quality control
- Electronic publication
- The World Wide Web
- Links
- Information flow in bioinformatics
- Curation, annotation, and quality control
- A database without effective modes of access is merely a data graveyard
- Database access
- Data mining
- Survey of databases in molecular biology
- Nucleic-acid sequence databases
- Protein sequence databases
- Databases of genetic diseases—OMIM and OMIA
- Databases of structures
- Classifications of protein structures
- Databases of metabolic pathways
- Expression and proteomics databases
- The literature as a database
- Lists of molecular biology databases and servers
- Computers and computer science
- Programming
- Database organization
- An example: a relational database of properties of amino acids
- Markup languages
- XML
- Programming languages and tools for database construction and access
- Traditional programming languages
- Scripting languages
- Program libraries specialized for molecular biology
- Java—computing over the web
- Natural language processing
- Natural language processing in mining the biomedical literature
- Recommended Reading
- There are many fine books and articles on bioinformatics. A few suggestions:
- The transition to electronic publishing
- Development of the Public Library of Science
- Sources for history and current status of databases in molecular biology
- XML
- Exercises, Problems, and Weblems
- Exercises
- Problems
- Weblems
- Chapter 4 Classical Genetics, Mapping, and Sequencing
- Classical genetics as background
- What is a gene?
- Maps and tour guides
- Genetic maps
- Linkage
- Linkage disequilibrium
- Linkage and linkage disequilibrium are closely related but distinct concepts
- Chromosome banding pattern maps
- Correlation between genetic linkage maps and chromosome structure
- Studies of evolutionary changes in karyotype
- Applications to diagnosis of disease
- High-resolution maps, based directly on DNA sequences
- Discovery of the structure of DNA
- DNA sequencing
- Frederick Sanger and the development of DNA sequencing
- DNA sequencing by termination of chain replication
- The Maxam–Gilbert chemical cleavage method
- Automation of DNA sequencing
- Classical methods for organizing large-scale sequencing projects
- Bring on the clones: hierarchical—or ‘BAC-to-BAC’—genome sequencing
- Whole-genome shotgun sequencing
- Comparison of BAC-to-BAC and whole-genome shotgun approaches
- Second-generation sequencing
- Goals for improvement in sequencing methods
- The octopus genome
- Third-generation sequencing
- Single-Molecule Real-Time sequencing (SMRT)
- Nanopore sequencing
- Concatenating Original Duplex for Error Correction (CODEC)
- Completion of the human genome
- The Y chromosome
- Life in the fast lane
- How much sequencing power is there in the world?
- Recommended Reading
- Some historical perspectives
- Linkage disequilibrium
- The following articles describe the recent advances that have produced the high-throughput sequencing platforms on which contemporary sequencing depends.
- Exercises, Problems, and Weblems
- Exercises
- Problems
- Weblems
- List of Key Terms
- Chapter 5 Evolution and Genomic Change
- Evolution is exploration
- Biological systematics
- Biological nomenclature
- Measurement of biological similarities and differences
- Molecular techniques
- Homologues and families
- Pattern matching—the basic tool of bioinformatics
- Sequence alignment
- The dot plot
- Dot plots and alignments
- Defining the optimum alignment
- Scoring schemes
- The BLOSUM matrices
- Scoring insertions and deletions, or ‘gap weighting’
- Varieties and extensions
- Approximate methods for quick screening of databases
- Multiple sequence alignments and pattern detection
- Pattern matching in three-dimensional structures
- Evolution of protein sequences, structures, functions
- The effects of single-site mutations
- Evolution of protein structure and function
- Divergence of function in the enolase superfamily
- Phylogeny
- Evolutionary trees
- Calculation of phylogenetic trees
- Clustering methods
- Cladistic methods
- The problem of varying rates of evolution
- Bayesian methods
- Short-circuiting evolution: genetic engineering
- Recommended Reading
- General presentations of phylogeny (Felsenstein is particularly strong on the history of the subject, expected from a scientist who has had such a long-term commitment to the field)
- The basis of sequence analysis
- Evolution of protein structure
- Phylogenetic relationships in eukaryotes
- It is possible to represent phylogenetic relationships in forms more general than tree structures
- Natural genetic engineering by Toxoplasma gondii
- Exercises, Problems, and Weblems
- Exercises
- Problems
- Weblems
- List of Key Terms
- Chapter 6 Comparative Genomics
- Unity and diversity of life
- Taxonomy based on sequences
- Sizes and organization of genomes
- Genome sizes
- Genome organization in eukaryotes
- Photosynthetic sea slugs: chloroplasts in animals
- How genomes differ
- Variation at the level of individual nucleotides
- Other types of changes affecting local regions of the genome
- Post-transcriptional events
- Duplications
- Duplication of genes
- Duplication can affect individual exons
- Family expansion: G-protein-coupled receptors
- Large-scale duplications
- Whole-genome duplication
- Comparisons at the chromosome level: synteny
- What makes us human?
- Genomes of chimpanzees and humans
- Genomes of mice and rats
- Model organisms for study of human diseases
- The genome of Caenorhabditis elegans
- The genome of Drosophila melanogaster
- Homologous genes in humans, worms, and flies
- Models of human disease
- Recommended Reading
- Origin of eukaryotes
- Papers treating some of the current debate in biological taxonomy and the strengths and weaknesses of barcoding, and a description of the database
- Detailed review of work on genome comparisons and what they tell us about genome contents and evolution
- How modern developments in biological data collection affect the use of model organisms in the study of human biology and disease
- The significance of duplications
- Molecular clocks
- Variable splicing
- RNA editing
- Exercises, Problems, and Weblems
- Exercises
- Problems
- Weblems
- List of Key Terms
- Chapter 7 Genomes of Prokaryotes and Viruses
- Evolution and phylogenetic relationships in prokaryotes
- Major types of prokaryotes
- Do we know the root of the tree of life?
- Genome organization in prokaryotes
- Replication and transcription
- Gene transfer
- Archaea
- The genome of Methanococcus jannaschii
- Life at extreme temperatures
- What choices do organisms have to adjust the thermal stability of their constituents?
- Comparative genomics of hyperthermophilic archaea: Thermococcus kodakarensis and Pyrococci
- General features of the genome
- Molecular physiology of T. kodakarensis
- Comparative genomics of T. kodakarensis
- Bacteria
- Genomes of pathogenic bacteria
- Genomics and the development of vaccines
- Viruses
- Nucleocytoplasmic large DNA viruses (or giant viruses)
- Viral genomes
- Recombinant viruses
- Viruses and evolution
- Influenza: a past and current threat
- Avian flu
- Drugs against influenza
- COVID-19
- ‘Ome, ome, on the range: metagenomics, the genomes in a coherent environmental sample
- Marine cyanobacteria—an in-depth study
- How are different Prochlorococcus strains adapted to differences in ambient light intensities and spectral distributions?
- Protection against photochemical damage
- Utilization of nitrogen sources
- Protection against predators and viruses
- Recommended Reading
- General discussions of prokaryotic classification
- Last universal common ancestor (LUCA) and related topics
- The history of the growth of oxygen in the atmosphere: an intersection between biochemistry and geology
- New approaches to vaccine design
- Genomics of viruses
- Metagenomics
- Exercises, Problems, and Weblems
- Exercises
- Problems
- Weblems
- Chapter 8 Genomes of Eukaryotes
- The origin and evolution of eukaryotes
- Evolution and phylogenetic relationships in eukaryotes
- The yeast genome
- The evolution of plants
- The Arabidopsis thaliana genome
- Genomes of animals
- The genome of the sea squirt (Ciona intestinalis)
- The genome of the pufferfish (Tetraodon nigroviridis)
- The genome of the Australian lungfish (Neoceratodus forsteri)
- The genome of the chicken (Gallus gallus domesticus)
- The genome of the platypus (Ornithorhynchus anatinus)
- The genome of the dog (Canis lupus familiaris)
- History of the dog
- Genome variation among breeds of dogs
- Comparison of dog, human, and mouse genomes
- Palaeosequencing—ancient DNA
- Recovery of DNA from ancient samples
- DNA from extinct birds
- The moas of New Zealand
- The dodo and the solitaire
- High-throughput sequencing of mammoth DNA
- The mammoth nuclear genome
- The phylogeny of elephants
- Recommended reading
- General discussions of topics in eukaryotic evolution, some in the form of collections of papers
- Whole-genome duplications
- An atlas of life forms, showing phylogenetic relationships and dates of divergence
- Sequencing of ancient DNA
- Exercises, Problems, and Weblems
- Exercises
- Problem
- Weblems
- Chapter 9 Genomics and Anthropology: Human Evolution, Migration, and Domestication of Plants and Animals
- Ancestry of Homo sapiens
- The Neandertal genome
- The Denisovan genome
- What do these data tell us?
- What have Neandertals and Denisovans done for us lately?
- Ancient populations and migrations
- Western civilization? ‘I think it would be a good idea’2
- Domestication of the dog
- Domestication of the horse
- Domestication of crops
- Maize (Zea mays)
- Rice (Oryza sativa)
- Control of flowering time
- History of rice domestication
- Chocolate (Theobroma cacao)
- The T. cacao genome
- Recommended reading
- Genomics and human evolution
- History of migrations
- Human migrations revealed by microbiology
- Databases of human mitochondrial sequences
- Database of human Y-chromosome sequences
- Domestication of animals
- Domestication of crop plants
- The contribution of genomics to understanding the history of agriculture
- Exercises, Problems, and Weblems
- Exercises
- Problems
- Weblems
- Chapter 10 The Impact of Genomics on Human Health and Disease
- Introduction
- Some diseases are associated with mutations in specific genes
- Haemoglobinopathies—molecular diseases caused by abnormal haemoglobins
- Sickle-cell disease
- Thalassaemias
- Phenylketonuria
- Alzheimer’s disease
- Identification of genes associated with inherited diseases
- Genome-wide association studies (GWAS)
- Genome-wide association studies of sickle-cell disease
- Genome-wide association studies of type 2 diabetes
- Genome-wide association studies of schizophrenia
- The human microbiome
- Treatment of abnormal microbiome composition
- Cancer genomics
- Mutations and cancer
- Whole-genome sequencing association studies of breast cancer
- Copy-number alterations in cancer
- Chromosomal aberrations
- Epigenetics and cancer
- MicroRNAs and cancer
- Immunotherapy for cancer
- Recommended reading
- Applications of genomics to understanding and treatment of disease
- Genome-wide association studies
- The human microbiome
- Genomics and cancer
- Exercises, Problems, and Weblems
- Exercises
- Problems
- Weblems
- List of Key Terms
- Chapter 11 Transcriptomics
- Introduction
- Applications of transcriptomics
- Microarrays
- Microarray data are semiquantitative
- RNAseq
- What information can RNAseq reveal, that is not contained in the genome sequence itself?
- Variable splicing in the retina
- Single-cell RNA sequencing
- Analysis of differential gene expression data
- Transcriptome databases
- Expression patterns in different physiological states
- Expression pattern changes in development
- Variation of expression patterns during the life cycle of Drosophila melanogaster
- Different life stages make different demands on different genes
- Flower formation in roses
- Regulation of pathways that produce scents in roses
- Colour: the elusive blue rose
- Expression patterns in learning and memory: long-term potentiation
- Conserved clusters of co-expressing genes
- Evolutionary changes in expression patterns
- Applications of transcriptomics in medicine
- Development of antibiotic resistance in bacteria
- Fighting back
- Childhood leukaemias
- The Encyclopedia of DNA Elements (ENCODE)
- Recommended reading
- Transcriptional regulation
- Microarrays
- RNA sequencing
- Applications
- The problem of bacterial drug resistance and the development of novel antibiotics
- The ENCODE project
- RNA sequencing
- Exercises, Problems, and Weblems
- Exercises
- Problems
- Weblems
- List of Key Terms
- Chapter 12 Proteomics
- Introduction
- Proteins are where the action is (much of it, anyway)
- Protein structure
- The chemical structure of proteins
- Non-ribosomal peptides
- Conformation of the polypeptide chain
- Protein folding patterns
- Supersecondary structures
- Domains
- Domain reassembly in evolution
- Disorder in proteins
- Post-translational modifications
- Why is there a common genetic code with 20 canonical amino acids?
- Protein purification
- Ammonium sulphate precipitation
- Size-exclusion chromatography
- Ion-exchange chromatography
- Affinity chromatography
- Specific expression of a target protein
- Polyacrylamide gel electrophoresis (PAGE)
- Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE)
- Mass spectrometry
- Identification of components of a complex mixture
- Protein sequencing by mass spectrometry
- Quantitative analysis of relative abundance
- Measuring deuterium exchange in proteins
- Experimental methods of protein determination
- X-ray crystallography of proteins
- Interpretation of the electron density: model and improvement
- The endgame—refinement
- How accurate are the structures?
- Nuclear magnetic resonance spectroscopy in structural biology
- Protein structure determination by NMR
- From the data to the structure
- Low-temperature electron microscopy (cryo-EM)
- Protein structure prediction
- Homology modelling
- A priori structure prediction
- Classifications of protein structures
- Structural Classification of Proteins (SCOP)
- SCOP2
- CATH
- Protein complexes and aggregates
- Protein aggregation diseases
- Alzheimer’s disease
- Prion diseases—spongiform encephalopathies
- Properties of protein–protein complexes
- Stoichiometry—what is the composition of the complex?
- Affinity—how stable is the complex?
- How are complexes organized in three dimensions?
- Multisubunit proteins
- Many proteins change conformation as part of the mechanism of their function
- Conformational change during enzymatic catalysis
- Arginine kinase
- Regulation of G protein activity
- Motor proteins
- The sliding filament mechanism of muscle contraction
- Allosteric regulation of protein function
- Cooperativity in haemoglobin oxygen binding
- Allosteric changes in haemoglobin
- Protein evolution at the lab bench
- Directed evolution
- Directed evolution of subtilisin E
- Enhancement of thermal stability by directed evolution
- Designed enzymes
- Recommended reading
- Two fine general references
- Historical review
- Reviews of current techniques in proteomics
- Protein structure determination
- State of the art in protein structure prediction
- Structural classifications of protein domains
- Protein complexes
- Directed evolution and protein design
- A companion volume to this one, treating the topics of this chapter in more detail:
- Non-ribosomal peptides
- Exercises, Problems, and Weblems
- Exercises
- Problems
- Weblems
- List of Key Terms
- Chapter 13 Metabolomics
- Introduction
- Classification and assignment of protein function
- The Enzyme Commission
- The Gene Ontology™ Consortium protein function classification
- Comparison of Enzyme Commission and Gene Ontology classifications
- Metabolic networks
- Databases of metabolic pathways
- EcoCyc
- Methionine synthesis in Escherichia coli
- The Kyoto Encyclopedia of Genes and Genomes (KEGG)
- The Human Metabolome Database
- Evolution and phylogeny of metabolic pathways
- Alignment and comparison of metabolic pathways
- Comparing linear metabolic pathways
- Reconstruction of metabolic networks
- Comparing non-linear metabolic pathways: the pentose phosphate pathway and the Calvin—Benson cycle
- Metabolomics in ecology
- Dynamic modelling of metabolic pathways
- Recommended reading
- General discussions of metabolomics
- Metabolomics of prokaryotes
- Description of concepts used for analysis of metabolic networks
- Metabolic network reconstruction
- Evolution of metabolic networks
- Modelling of network traffic
- Metabolomics databases
- A ‘niche’ approach, but one of which the reader should be aware
- Exercises, Problems, and Weblems
- Exercises
- Problems
- Weblems
- List of Key Terms
- Chapter 14 Systems Biology
- Introduction
- Regulatory mechanisms
- Two parallel networks: physical and logical
- Networks and graphs
- Robustness and redundancy
- Connectivity in networks
- Dynamics, stability, and robustness
- Protein complexes and aggregates
- Protein interaction networks
- Protein–DNA interactions
- DNA–protein complexes mediate several types of processes
- Structural themes in protein–DNA binding and sequence recognition
- Examples of protein–DNA interactions
- Bacteriophage T7 DNA polymerase
- Some protein–DNA interactions require breaking the DNA chain
- Some protein–DNA complexes that regulate gene transcription
- λ cro
- The eukaryotic homeodomain antennapedia
- Leucine zippers as transcriptional regulators
- Zinc fingers
- The E. coli Met repressor
- The TATA-box binding protein
- p53 is a tumour suppressor
- Regulatory networks
- Structures of regulatory networks
- Structural biology of regulatory networks
- Gene regulation
- The transcriptional regulatory network of Escherichia coli
- ‘The road not taken …’ some real-world decision making
- The genetic switch of bacteriophage λ
- The materials
- How to ‘throw’ the switch
- Regulation of the lactose operon in E. coli
- The diauxic shift in Saccharomyces cerevisiae
- The genetic regulatory network of Saccharomyces cerevisiae
- Adaptability of the yeast regulatory network
- Relationships among networks
- Recommended reading
- Networks in general
- Systems biology of important biological networks
- Evolution of networks
- Exercises, Problems, and Weblems
- Exercises
- Problems
- Weblems
- List of Key Terms
- Epilogue
- Glossary
- List of Illustrations
- List of Tables
- Images
- Chapter 1 Introduction and Background
- Chapter 2 The Human Genome Project: Achievements and Applications
- Chapter 3 Bioinformatics
- Chapter 4 Classical Genetics, Mapping, and Sequencing
- Chapter 5 Evolution and Genomic Change
- Chapter 6 Comparative Genomics
- Chapter 7 Genomes of Prokaryotes and Viruses
- Chapter 8 Genomes of Eukaryotes
- Chapter 9 Genomics and Anthropology: Human Evolution, Migration, and Domestication of Plants and Animals
- Chapter 10 The Impact of Genomics on Human Health and Disease
- Chapter 11 Transcriptomics
- Chapter 12 Proteomics
- Chapter 13 Metabolomics
- Chapter 14 Systems Biology