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Human Molecular Genetics

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ISBN-10: 0471330612

ISBN-13: 9780471330615

Edition: 2nd 1999

Authors: Tom Strachan, Andrew P. Read

List price: $91.95
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Book details

List price: $91.95
Edition: 2nd
Copyright year: 1999
Publisher: John Wiley & Sons, Incorporated
Publication date: 10/29/1999
Binding: Paperback
Pages: 640
Size: 8.50" wide x 11.50" long x 1.25" tall
Weight: 3.498
Language: English

Abbreviations
Preface to the first edition
Preface to the second edition
Before we start -- genetic data and the Internet
All students of human molecular genetics should be using the Internet
The World Wide Web is the primary way of using the Internet
Useful Internet starting points for human molecular genetics
The World Wide Web gives access to most human genetic data
Comprehensive DNA and protein sequence databases cover all organisms
OMIM is the standard database of human mendelian characters
Medline is the main way to locate published papers on a topic
Searching for a web page
DNA structure and gene expression
Building blocks and chemical bonds in DNA, RNA and polypeptides
DNA structure and replication
Examples of the importance of hydrogen bonding in nucleic acids and proteins
RNA transcription and gene expression
RNA processing
Translation, post-translational processing and protein structure
Chromosomes in cells
Organization and diversity of cells
Anatomy of animal cells
Development
A brief outline of animal development
The diversity of human cells
Structure and function of chromosomes
Mitosis and meiosis are the two types of cell division
Studying human chromosomes
Chromosome banding
Chromosome nomenclature
Chromosome abnormalities
Nomenclature of chromosome abnormalities
Genes in pedigrees
Mendelian pedigree patterns
Mendelian pedigree patterns
The complementation test to discover whether two recessive characters are determined by allelic genes
Complications to the basic pedigree patterns
Factors affecting gene frequencies
Hardy-Weinberg equilibrium genotype frequencies for allele frequencies p (A[subscript 1]) and q (A[subscript 2])
The Hardy-Weinberg distribution can be used (with caution) to calculate carrier frequencies and simple risks for counseling
Mutation-selection equilibrium
Selection in favor of heterozygotes for cystic fibrosis
Nonmendelian characters
Cell-based DNA cloning
Fundamentals of DNA technology and the importance of DNA cloning
Principles of cell-based DNA cloning
Restriction endonucleases and modification-restriction systems
Oligonucleotide linkers
Nonsense suppressor mutations
Vector systems for cloning different sizes of DNA fragments
Cloning systems for preparing single-stranded DNA and for studying gene expression
Nucleic acid hybridization assays
Preparation of nucleic acid probes
Principles of autoradiography
Principles of nucleic acid hybridization
Fluorescence labeling and detection systems
Competition hybridization and Cot-1 DNA
Nucleic acid hybridization assays using cloned DNA probes to screen uncloned nucleic acid populations
Standard and reverse nucleic acid hybridization assays
Nucleic acid hybridization assays using cloned target DNA, and microarray hybridization technology
Evolution and applications of DNA microarrays ('DNA chips')
PCR, DNA sequencing and in vitro mutagenesis
Basic features of PCR
Proofreading by DNA polymerase-associated 3' =] 5' exonuclease activity
Applications of PCR
DNA sequencing
In vitro site-specific mutagenesis
Organization of the human genome
General organization of the human genome
The limited autonomy of the mitochondrial genome
Organization and distribution of human genes
Human gene organization
Human multigene families and repetitive coding DNA
Pseudogenes and gene fragments
Extragenic repeated DNA sequences and transposable elements
Classes of mammalian sequence which undergo transposition through an RNA intermediate
Human gene expression
An overview of gene expression in human cells
Spatial and temporal restriction of gene expression in mammalian cells
Control of gene expression by binding of trans-acting protein factors to cis-acting regulatory sequences in DNA and RNA
Classes of cis-acting sequence elements involved in regulating transcription of polypeptide-encoding genes
Alternative transcription and processing of individual genes
The classical view of a gene is no longer valid
Alternative splicing can alter the functional properties of a protein
Asymmetry as a means of establishing differential gene expression and DNA methylation as means of perpetuating differential expression
CpG islands
Long-range control of gene expression and imprinting
Mechanisms resulting in monoallelic expression from biallelic genes in human (mammalian) cells
The nonequivalence of the maternal and paternal genomes
The unique organization and expression of Ig and TCR genes
Instability of the human genome: mutation and DNA repair
An overview of mutation, polymorphism, and DNA repair
Simple mutations
Mechanisms which affect the population frequency of alleles
Classes of single base substitution in polypeptide-encoding DNA
Genetic mechanisms which result in sequence exchanges between repeats
Pathogenic mutations
How are new mitochondrial mutations fixed (i.e. achieve a frequency of 100% in a population)?
The pathogenic potential of repeated sequences
DNA repair
Physical and transcript mapping
Low resolution physical mapping
Selecting for the chromosome contents of hybrids
Chromosome painting
High resolution physical mapping: chromatin and DNA fiber FISH and restriction mapping
Assembly of clone contigs
The importance of sequence tagged sites (STSs)
Constructing transcript maps and identifying genes in cloned DNA
Commonly used methods for identifying genes in cloned DNA
Genetic mapping of mendelian characters
Recombinants and nonrecombinants
Genetic markers
The development of human genetic markers
Informative and uninformative meioses
Two-point mapping
Calculation of lod scores
Bayesian calculation of linkage threshold
Multipoint mapping is more efficient than two-point mapping
Standard lod score analysis is not without problems
Genetic mapping of complex characters
Parametric linkage analysis and complex diseases
Nonparametric linkage analysis does not require a genetic model
Association is in principle quite distinct from linkage, but where the family and the population merge, linkage and association merge
The transmission disequilibrium test (TDT)
Linkage disequilibrium as a mapping tool
Thresholds of significance are an important consideration in analysis of complex diseases
Sample sizes needed to find a disease susceptibility locus by a whole genome scan using either affected sib pairs (ASP) or the transmission disequilibrium test (TDT)
Strategies for complex disease mapping usually involve a combination of linkage and association techniques
Genome projects
The history, organization, goals and value of the Human Genome Project
Genetic and physical mapping of the human genome
Human gene and DNA segment nomenclature
Cooperation, competition and controversy in the genome projects
Model organism and other genome projects
Model organisms for which genome projects are considered particularly relevant to the Human Genome Project
Life in the post-genome (sequencing) era
Our place in the tree of life
Evolution of the mitochondrial genome and the origin of eukaryotic cells
The three kingdoms of life
Evolution of the eukaryotic nuclear genome: genome duplication and large-scale chromosomal alterations
Paralogy, orthology and homology
Evolution of the human sex chromosomes
Evolution of human DNA sequence families and DNA organization
Evolution of gene structure
Intron groups and intron phases
What makes us human? Comparative mammalian genome organization and the evolution of modern humans
Identifying human disease genes
Principles and strategies in identifying disease genes
Position-independent strategies for identifying disease genes
In positional cloning, disease genes are identified using only knowledge of their approximate chromosomal location
Transcript mapping: how to identify expressed sequences within genomic clones from a candidate region
Pointers to the presence of large-scale mutations
Position effects - a pitfall in disease gene identification
Positional candidate strategies identify candidate genes by a combination of their map position and expression, function or homology
Mapping mouse genes
Confirming a candidate gene
Molecular pathology
Introduction
The main classes of mutation
There are rules for the nomenclature of mutations and databases of mutations
A nomenclature for describing the effect of an allele
Nomenclature for describing mutations
A first classification of mutations is into loss of function vs gain of function mutations
Loss of function mutations
Guidelines for deciding whether a DNA sequence change is pathogenic
Hemoglobinopathies
Molecular pathology of Prader-Willi and Angelman syndromes
Gain of function mutations
Unstable expanding repeats - a novel cause of disease
Laboratory diagnosis of fragile X
Molecular pathology: from gene to disease
Molecular pathology: from disease to gene
Molecular pathology of chromosomal disorders
Genetic testing in individuals and populations
Direct testing is like any other path lab investigation: a sample from the patient is tested to see if it is normal or abnormal
Gene tracking
Gene tracking: four stages in the investigation of a late-onset autosomal dominant disease where direct mutation detection is not possible
Use of Bayes' theorem for combining probabilities
Population screening
DNA profiling can be used for identifying individuals and determining relationships
Cancer genetics
Cancer is the natural end-state of multicellular organisms
Mutations in cancer cells typically affect a limited number of pathways
Two ways of making a series of successive mutations more likely
Oncogenes
Activation of proto-oncogenes
Tumor suppressor genes
Two-hit mechanisms may explain patchy mendelian phenotypes
Control of the cell cycle
Control of the integrity of the genome
The multistep evolution of cancer
Complex diseases: theory and results
Deciding whether a nonmendelian character is genetic: the role of family, twin and adoption studies
Genetic differences between identical twins
Polygenic theory of quantitative traits
Two common misconceptions about regression to the mean
Partitioning of variance
Polygenic theory of discontinuous characters
Segregation analysis allows analysis of characters that are anywhere on the spectrum between purely mendelian and purely polygenic
Correcting the segregation ratio
Seven examples illustrate the varying success of genetic dissection of complex diseases
Applications of genetic insights into complex diseases
Studying human gene structure, expression and function using cultured cells and cell extracts
Gene structure and transcript mapping studies
Obtaining gene clones for studying human gene structure, expression and function
Studying gene expression using cultured cells or cell extracts
Obtaining antibodies
Confocal fluorescence microscopy
Identifying regulatory sequences through the use of reporter genes and DNA-protein interactions
Methods for transferring genes into cultured animal cells
Investigating gene function by identifying interactions between a protein and other macromolecules
Genetic manipulation of animals
An overview of genetic manipulation of animals
The creation and applications of transgenic animals
Isolation and manipulation of mammalian embryonic stem cells
Use of mouse embryonic stem cells in gene targeting and gene trapping
Creating animal models of disease using transgenic technology and gene targeting
The potential of animals for modeling human disease
Manipulating animals by somatic cell nuclear transfer
Gene therapy and other molecular genetic-based therapeutic approaches
Principles of molecular genetic-based therapies and treatment with recombinant proteins or genetically engineered vaccines
General gene therapy strategies
Treatment using conventional animal or human products can be hazardous
The technology of classical gene therapy
Cell therapy
Therapeutics based on targeted inhibition of gene expression and mutation correction in vivo
Gene therapy for inherited disorders
Gene therapy for neoplastic disorders and infectious disease
The ethics of human gene therapy
Glossary
Indexes