Human Molecular Genetics,9780815341826

Human Molecular Genetics

by ;
Edition: 3rd
ISBN13: 9780815341826
ISBN10: 0815341822
Format: Hardcover
Pub. Date: 2003-11-21
Publisher(s): Garland Science
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Summary

Following the completion of the Human Genome Project the content and organization of the third edition of Human Molecular Genetics has been thoroughly revised. * Part One (Chapters 1-7) covers basic material on DNA structure and function, chromosomes, cells and development, pedigree analysis and the basic techniques used in the laboratory. * Part Two (Chapters 8-12) discusses the various genome sequencing projects and the insights they provide into the organization, expression, variation and evolution of our genome. * Part Three (Chapters 13-18) focuses on mapping, identifying and diagnosing the genetic causes of mendelian and complex diseases and cancer. * Part Four (Chapters 19-21) looks at the wider horizons of functional genomics, proteomics, bioinformatics, animal models and therapy. There are new chapters on cells and development and on functional genomics. The sections on complex diseases have been completely rewritten and reorganized, as hasthe chapter on Genome Projects. Other changes include a new section on molecular phylogenetics (Chapter 12) and the introduction of 'Ethics Boxes' to discuss some of the implications of the new knowledge. Virtually every page has been revised and updated to take account of the stunning developments of the past four years since the publication of the last edition of Human Molecular Genetics. features: * Integration of Human Genome Project data throughout the book * Two new chapters 'Cells and Development' (Chapter 3) and 'Beyond the Genome Project: Functional Genomics, Proteomics and Bioinformatics' (Chapter 19) * Completely rewritten and reorganized coverage of complex disease genetics * Increased emphasis on gene function and on applications of genetic knowledge, including ethical issues * More prominence given to novel approaches to treating disease, such as cell-based therapies, pharmacogenomics, and personalized medicine * Special topic boxes that include detailedcoverage of ethical, legal and social issues, including eugenics, genetic testing and discrimination, germ-line gene therapy and genetic enhancement, and human cloning * Contains two indices: a general index and one that contains names of diseases and disorders.

Author Biography

Andrew Read is Professor of Human Genetics at Manchester University.

Table of Contents

Abbreviations xxiii
Preface xxvii
Supplementary learning aids xxviii
Before we start -- Intelligent use of the Internet xxix
PART ONE: The Basics
1(204)
DNA structure and gene expression
3(30)
Building blocks and chemical bonds in DNA, RNA and polypeptides
4(4)
DNA, RNA and polypeptides are large polymers defined by a linear sequence of simple repeating units
4(2)
Covalent bonds confer stability; weaker noncovalent bonds facilitate intermolecular associations and stabilize structure
6(2)
DNA structure and replication
8(5)
The structure of DNA is an antiparallel double helix
8(2)
Examples of the importance of hydrogen bonding in nucleic acids and proteins
10(1)
DNA replication is semi-conservative and synthesis of DNA strands is semi-discontinuous
10(1)
The DNA replication machinery in mammalian cells is complex
10(2)
Major classes of proteins used in the DNA replication machinery
12(1)
Viral genomes are frequently maintained by RNA replication rather than DNA replication
13(1)
RNA transcription and gene expression
13(6)
The flow of genetic information in cells is almost exclusively one way: DNA RNA protein
13(2)
Only a small fraction of the DNA in complex organisms is expressed to give a protein or RNA product
15(1)
During transcription genetic information in some DNA segments (genes) specifies RNA
16(1)
Cis-acting regulatory elements and trans-acting transcription factors are required in eukaryotic gene expression
17(2)
Tissue-specific gene expression involves selective activation of specific genes
19(1)
RNA processing
19(4)
RNA splicing removes nonessential RNA sequences from the primary transcript
19(3)
Specialized nucleotides are added to the 5' and 3' ends of most RNA polymerase II transcripts
22(1)
Translation, post-translational processing and protein structure
23(10)
During translation mRNA is decoded on ribosomes to specify the synthesis of polypeptides
23(2)
The genetic code is degenerate and not quite a universal code
25(1)
Post-translational modificatins include chemical modifications of some amino acids and polypeptide cleavage
26(2)
Protein secretion and intracellular export is controlled by specific localization signals or by chemical modifications
28(1)
Protein structure is highly varied and not easily predicted from the amino acid sequence
29(4)
Chromosome structure and function
33(26)
Ploidy and the cell cycle
34(1)
Structure and function of chromosome
34(6)
Packaging of DNA into chromosomes requires multiple hierarchies of DNA folding
35(1)
Individual chromosomes occupy nonoverlapping territories in an interphase nucleus
35(1)
Chromosomes as functioning organelles: the pivotal role of the centromere
36(1)
The mitotic spindle and its components
37(1)
Chromosomes as functioning organelles: origins of replication
38(1)
Chromosomes as functioning organelles: the telomeres
39(1)
Heterochromatin and euchromatin
40(1)
Mitosis and meiosis are the two types of cell division
40(4)
Mitosis is the normal form of cell division
40(1)
Meiosis is a specialized form of cell division giving rise to sperm and egg cells
41(3)
X-Y pairing and the pseudoautosomal regions
44(1)
Studying human chromosomes
44(7)
Mitotic chromosomes can be seen in any dividing cell, but meiotic chromosomes are hard to study in humans
44(4)
Chromosome banding
48(1)
Molecular cytogenetics: chromosome FISH
48(1)
Human chromosome nomenclature
49(1)
Chromosome painting, molecular karyotyping and comparative genome hybridization
49(2)
Chromosome abnormalities
51(8)
Types of chromosomal abnormality
51(1)
Numerical chromosomal abnormalities involve gain or loss of complete chromosomes
52(1)
Nomenclature of chromosome abnormalities
53(1)
Structural chromosomal abnormalities result from misrepair of chromosome breaks or from malfunction of the recombination system
54(3)
Apparently normal chromosomal complements may be pathogenic if they have the wrong parental origin
57(2)
Cells and development
59(42)
The structure and diversity of cells
60(6)
Prokaryotes and eukaryotes represent the fundamental division of cellular life forms
60(1)
Cell size and shape can vary enormously, but rates of diffusion fix some upper limits
61(1)
In multicellular organisms, there is a fundamental distinction between somatic cells and the germ line
61(1)
Intracellular organization of animal cells
62(2)
The cytoskeleton: the key to cell movement and cell shape and a major framework for intracellular transport
64(1)
In multicellular organisms, no two cells carry exactly the same DNA sequence
64(1)
Cells from multicellular organisms can be studied in situ or in culture
65(1)
Cell interactions
66(5)
Communication between cells involves the perception of signaling molecules by specific receptors
66(1)
Activated receptors initiate signal transduction pathways that may involve enzyme cascades or second messengers, and result in the activation or inhibition of transcription factors
67(1)
The organization of cells to form tissues requires cell adhesion
67(3)
The extracellular matrix provides a scaffold for all tissues in the body and is also an important source of signals that control cell behavior
70(1)
An overview of development
71(1)
The specialization of cells during development
72(7)
Cell specialization involves an irreversible series of hierarchical decisions
72(1)
Animal models of development
73(1)
The choice between alternative fates may depend on lineage or position
73(1)
Twinning in human embryos
74(1)
Stem cells are self-renewing progenitor cells
74(1)
Where our tissues come from -- the developmental hierarchy in mammals
75(1)
The diversity of human cells
76(1)
A variety of tissue stem cells are known to exist but much remains to be learned about them
77(1)
Embryonic stem (ES) cells have the potential to form any tissue
78(1)
The differentiation potential of tissue stem cells is controversial
79(1)
Pattern formation in development
79(2)
Emergence of the body plan is dependent on axis specification and polarization
80(1)
Homeotic mutations reveal the molecular basis of positional identity
80(1)
Pattern formation often depends on signal gradients
80(1)
Morphogenesis
81(5)
Morphogenesis can be driven by changes in cell shape and size
81(1)
Polarizing the mammalian embryo -- signals and gene products
82(1)
Major morphogenetic changes in the embryo result from diferential cell affinity
82(3)
Cell proliferation and programmed cell death (apoptosis) are important morphogenetic mechanisms
85(1)
Early human development: fertilization to gastrulation
86(8)
Fertilization activates the egg and brings together the nuclei of sperm and egg to form a unique individual
86(1)
Cleavage partitions the zygote into many smaller cells
87(1)
Only a small percentage of the cells in the early mammalian embryo gives rise to the mature organism
88(1)
Implantation
88(1)
Gastrulation is a dynamic process whereby cells of the epiblast give rise to the three germ layers
88(1)
Extra-embryonic membranes and the placenta
89(4)
Sex determination: genes and the environment in development
93(1)
Neural development
94(3)
The nervous system develops after the ectoderm is induced to differentiate by the underlying mesoderm
94(1)
Pattern formation in the neural tube involves the coordinated expression of genes along two axes
94(1)
Neuronal differentiation involves the combinatorial activity of transcription factors
95(2)
Conservation of developmental pathways
97(4)
Many human diseases are caused by the failure of normal developmental processes
97(1)
Developmental processes are highly conserved at both the single gene level and the level of complete pathways
98(3)
Genes in pedigrees and populations
101(20)
Monogenic versus multifactorial inheritance
102(1)
Mendelian pedigree patterns
102(4)
Dominance and recessiveness are properties of characters, not genes
102(1)
There are five basic Mendelian pedigree patterns
102(2)
Characteristics of the Mendelian patterns of inheritance
104(1)
The mode of inheritance can rarely be defined unambiguously in a single pedigree
104(1)
One gene--one enzyme does not imply one gene--one syndrome
105(1)
Mitochondrial inheritance gives a recognizable matrilineal pedigree pattern
106(1)
The complementation test to discover whether two recessive characters are determined by allelic genes
106(1)
Complications to the basic Mendelian pedigree patterns
106(5)
Common recessive conditions can give a pseudo-dominant pedigree pattern
106(1)
Failure of a dominant condition to manifest is called nonpenetrance
106(1)
Many conditions show variable expression
107(2)
For imprinted genes, expression depends on parental origin
109(1)
Male lethality may complicate X-linked pedigrees
109(1)
New mutations often complicate pedigree interpretation, and can lead to mosaicism
109(2)
Genetics of multifactorial characters: the polygenic-threshold theory
111(6)
Some history
111(1)
Polygenic theory of quantitative traits
112(2)
Two common misconceptions about regression to the mean
114(1)
Partitioning of variance
115(1)
Polygenic theory of discontinuous characters
115(1)
Counseling in non-Mendelian conditions uses empiric risks
116(1)
Factors affecting gene frequencies
117(4)
There can be a simple relation between gene frequencies and genotype frequencies
117(1)
Genotype frequencies can be used (with caution) to calculate mutation rates
117(1)
Hardy-Weinberg equilibrium genotype frequencies for allele frequencies p(A1) and q (A2)
117(1)
The Hardy-Weinberg distribution can be used (with caution) to calculate carrier frequencies and simple risks for counseling
118(1)
Mutation-selection equilibrium
118(1)
Heterozygote advantage can be much more important than recurrent mutation for determining the frequency of a recessive disease
118(1)
Selection in favor of heterozygotes for CF
119(2)
Amplifying DNA: PCR and cell-based DNA cloning
121(34)
The importance of DNA cloning
122(1)
PCR: basic features and applications
123(6)
Principles of basic PCR and reverse transcriptase (RT) PCR
123(1)
A glossary of PCR methods
124(1)
PCR has two major limitations: short sizes and low yields of products
125(2)
General applications of PCR
127(1)
Some PCR reactions are designed to permit multiple amplification products and to amplify previously uncharacterized sequences
128(1)
Principles of cell-based DNA cloning
129(9)
An overview of cell-based DNA cloning
129(1)
Restriction endonucleases and modification-restriction systems
129(1)
Restriction endonucleases enable the target DNA to be cut into manageable pieces which can be joined to similarly cut vector molecules
130(3)
Introducing recombinant DNA into recipient cells provides a method for fractionating a complex starting DNA population
133(1)
DNA libraries are a comprehensive set of DNA clones representing a complex starting DNA population
133(2)
Recombinant screening is often achieved by insertional inactivation of a marker gene
135(3)
Nonsense suppressor mutations
138(1)
The importance of sequence tagged sites (STSs)
138(1)
Cloning systems for amplifying different sized fragments
138(6)
Standard plasmid vectors provide a simple way of cloning small DNA fragments in bacterial (and simple eukaryotic) cells
139(1)
Lambda and cosmid vectors provide an efficient means of cloning moderately large DNA fragments in bacterial cells
140(2)
Large DNA fragments can be cloned in bacterial cells using vectors based on bacteriophage P1 and F factor plasmids
142(1)
Yeast artificial chromosomes (YACs) enable cloning of megabase fragments
143(1)
Cloning systems for producing single-stranded and mutagenized DNA
144(3)
Single-stranded DNA for use in DNA sequencing is obtained using M13 or phagemid vectors or by linear PCR amplification
144(2)
Oligonucleotide mismatch mutagenesis can create a predetermined single nucleotide change in any cloned gene
146(1)
PCR-based mutagenesis includes coupling of desired sequences or chemical groups to a target sequence and site-specific mutagenesis
146(1)
Cloning systems designed to express genes
147(8)
Large amounts of protein can be produced by expression cloning in bacterial cells
147(3)
Phage display is a form of expression cloning in which proteins are expressed on bacterial cell surfaces
150(1)
Eukaryotic gene expression is carried out with greater fidelity in eukaryotic cell lines
150(2)
Transferring genes into cultured animal cells
152(3)
Nucleic acid hybridization: principles and applications
155(26)
Preparation of nucleic acid probes
156(5)
Nucleic acids can conveniently be labeled in vitro by incorporation of modified nucleotides
156(1)
Nucleic acids can be labeled by isotopic and nonisotopic methods
157(2)
Principles of autoradiography
159(2)
Principles of nucleic acid hybridization
161(7)
Nucleic acid hybridization is a method for identifying closely related molecules within two nucleic acid populations
161(3)
Fluorescence labeling and detection systems
164(1)
The kinetics of DNA reassociation are defined by the product of DNA concentration and time (Cot)
164(2)
A glossary of nucleic acid hybridization
166(1)
A wide variety of nucleic acid hybridization assays can be used
167(1)
Nucleic acid hybridization assays using cloned DNA probes to screen uncloned nucleic acid populations
168(6)
Dot-blot hybridization, a rapid screening method, often employs allele-specific oligonucleotide probes
168(1)
Standard and reverse nucleic acid hybridization assays
169(1)
Southern and Northern blot hybridizations detect nucleic acids that have been size-fractionated by gel electrophoresis
169(2)
Pulsed field gel electrophoresis extends Southern hybridization to include detection of very large DNA molecules
171(1)
In in situ hybridization probes are hybridized to denatured DNA of a chromosome preparation or RNA of a tissue section fixed on a glass slide
172(2)
Hybridization assays using cloned target DNA and microarrays
174(7)
Colony blot and plaque lift hybridization are methods for screening separated bacterial colonies or plaques
174(1)
Gridded high density arrays of transformed cell clones or DNA clones has greatly increased the efficiency of DNA library screening
175(1)
DNA microarray technology has enormously extended the power of nucleic acid hybridization
175(6)
Analyzing DNA and gene structure, variation and expression
181(24)
Sequencing and genotyping DNA
182(4)
Standard DNA sequencing involves enzymatic DNA synthesis using base-specific dideoxynucleotide chain terminators
182(1)
Producing single-stranded DNA sequencing templates
182(1)
Automated DNA sequencing and microarray-based re-sequencing
183(1)
Basic genotyping of restriction site polymorphisms and variable number of tandem repeat polymorphisms
183(3)
Identifying genes in cloned DNA and establishing their structure
186(4)
Common classes of DNA polymorphism which are amenable to simple genotyping methods
187(1)
Exon trapping identifies expressed sequences by using an artificial RNA splicing assay
187(1)
cDNA selection identifies expressed sequences genomic clones by heteroduplex formation
188(1)
Achieving full-length cDNA sequences: overlapping clone sets, and RACE-PCR amplification
188(1)
Mapping transcription start sites and defining exon-intron boundaries
189(1)
Studying gene expression
190(15)
Principles of expression screening
190(2)
Database homology searching
192(1)
Hybridization-based gene expression analyses: from single gene analyses to whole genome expression screening
193(4)
PCR-based gene expression analyses: RT-PCR and mRNA differential display
197(1)
Protein expression screens typically use highly specific antibodies
198(2)
Obtaining antibodies
200(2)
Autofluorescent protein tags provided a powerful way of tracking subcellular localization of proteins
202(3)
PART TWO: The human genome and its relationship to other genomes
205(190)
Genome projects and model organisms
207(32)
The ground-breaking importance of genome projects
208(2)
Genome projects prepared the way for systematic studies of the Universe within
208(1)
The medical and scientific benefits of the genome projects are expected to be enormous
208(1)
A genomics glossary
209(1)
Background and organization of the Human Genome Project
210(2)
DNA polymorphisms and new DNA cloning technologies paved the way for sequencing our genome
210(1)
The Human Genome Project was mainly conducted in large genome centers with high-throughput sequencing capacity
210(2)
How the human genome was mapped and sequenced
212(14)
The first useful human genetic maps were based on microsatellite markers
212(1)
Human gene and DNA segment nomenclature
212(1)
Major milestones in mapping and sequencing the human genome
213(1)
The first high resolution physical maps of the human genome were based on clone contings and STS landmarks
213(2)
Hybrid cell mapping
215(2)
The final stage of the Human Genome Project was crucially dependent on BAC/PAC clone contigs
217(1)
Physical mapping by building clone contigs
218(2)
The first high density human gene maps were based on EST markers
220(1)
Co-operation, competition and controversy in the genome projects
220(1)
The draft human genome sequence suggested 30 000-35 000 human genes, but getting a precise total is difficult
221(3)
The final stages of the Human Genome Project: gene annotation and gene ontology
224(1)
Analyses of human genome sequence variation are important for anthropological and medical research
225(1)
Without proper safeguards, the Human Genome Project could lead to discrimination against carriers of disease genes and to a resurgence of eugenics
225(1)
Genome projects for model organisms
226(13)
There is a huge diversity of prokaryotic genome projects
226(1)
The S.cerevisiae genome project was the first of many successful protist genome projects
226(1)
Model unicellular organisms
227(1)
The Caenorhabditis elegans genome project was the first animal genome project to be completed
228(1)
Metazoan genome projects are mostly focusing on models of development and disease
229(1)
Model multicellular animals for understanding development, disease and gene function
230(9)
Organization of the human genome
239(36)
General organization of the human genome
240(7)
An overview of the human genome
240(1)
The mitochondrial genome consists of a small circular DNA duplex which is densely packed with genetic information
241(1)
Genome copy number variation in human cells
242(1)
The limited autonomy of the mitochondrial genome
243(1)
The nuclear genome consists of 24 different DNA molecules corresponding to the 24 different human chromosomes
244(1)
The human genome contains about 30 000--35 000 unevenly distributed genes but precise numbers are uncertain
245(1)
DNA methylation and CpG islands
246(1)
Organization, distribution and function of human RNA genes
247(6)
A total of about 1200 human genes encode rRNA or tRNA and are mostly organized into large gene clusters
247(2)
Small nuclear RNA and small nucleolar RNA are encoded by mostly dispersed, moderately large gene families
249(1)
Anticodon specificity of eukaryotic cytoplasmic tRNAs
249(1)
MicroRNAs and other novel regulatory RNAs are challenging preconceptions on the extent of RNA function
250(3)
Organization, distribution and function of human polypeptide-encoding genes
253(12)
Human genes show enormous variation in size and internal organization
253(1)
Functionally similar genes are occasionally clustered in the human genome, but are more often dispersed over different chromosomes
254(1)
Human genome and human gene statistics
255(1)
Overlapping genes, genes-within-genes and polycistronic transcription units are occasionally found in the human genome
256(1)
Polypeptide-encoding gene families can be classified according to the degree and extent of sequence relatedness in family members
257(2)
Genes in human gene families may be organized into small clusters, widely dispersed or both
259(3)
Pseudogenes, truncated gene copies and gene fragments are commonly found in multigene families
262(3)
Human proteome classification has begun but the precise functions of many human proteins remain uncertain
265(1)
Tandemly repeated noncoding DNA
265(3)
Satellite DNA consists of very long arrays of tandem repeats and can be separated from bulk DNA by density gradient centrifugation
265(2)
Minisatellite DNA is composed of moderately sized arrays of tandem repeats and is often located at or close to telomeres
267(1)
Microsatellite DNA consists of short arrays of simple tandem repeats and is dispersed throughout the human genome
268(1)
Interespersed repetitive noncoding DNA
268(7)
Transposon-derived repeats make up > 40% of the human genome and mostly arose through RNA intermediates
268(2)
Some human LINE1 elements are actively transposing and enable transposition of SINES, processed pseudogenes and retrogenes
270(1)
Alu repeats occur more than once every 3 kb in the human genome and may be subject to positive selection
270(5)
Human gene expression
275(40)
An overview of gene expression in human cells
276(1)
Spatial and temporal restriction of gene expression in mammalian cells
276(1)
Control of gene expression by binding of trans-acting protein factors to cis-acting regulatory sequences in DNA and RNA
277(14)
Histone modification and chromatin remodeling facilitate access to chromatin by DNA-binding factors
278(1)
Ubiquitous transcription factors are required for transcription by RNA polymerases I and III
279(1)
Transcription by RNA polymerase II requires complex sets of cis-acting regulatory sequences and tissue-specific transcription factors
280(2)
Transcription factors contain conserved structural motifs that permit DNA binding
282(1)
Classes of cis-acting sequence elements involved in regulating transcription of polypeptide-encoding genes
283(2)
A variety of mechanisms permit transcriptional regulation of gene expression in response to external stimuli
285(3)
Translational control of gene expression can involve recognition of UTR regulatory sequences by RNA-binding proteins
288(3)
Alternative transcription and processing of individual genes
291(3)
The use of alternative promoters can generate tissue-specific isoforms
291(1)
Human genes are prone to alternative splicing and alternative polyadenylation
292(1)
RNA editing is a rare form of processing whereby base-specific changes are introduced into RNA
293(1)
Alternative splicing can alter the functional properties of a protein
293(1)
Differential gene expression: origins through asymmetry and perpetuation through epigenetic mechanisms such as DNA methylation
294(4)
Selective gene expression in cells of mammalian embryos most likely develops in response to short range cell-cell signaling events
295(1)
DNA methylation is an important epigenetic factor in perpetuating gene repression in vertebrate cells
295(2)
Animal DNA methylation may provide defense against transposons as well as regulating gene expression
297(1)
Long range control of gene expression and imprinting
298(8)
Chromatin structure may exert long-range control over gene expression
298(1)
Expression of individual genes in gene clusters may be co-ordinated by a common locus control region
299(1)
Some human genes show selective expression of only one of the two parental alleles
300(1)
Genomic imprinting involves differences in the expression of alleles according to parent of origin
301(1)
Mechanisms resulting in monoallelic expression from biallelic genes in human cells
302(1)
The nonequivalence of the maternal and paternal genomes
302(1)
The mechanism of genomic imprinting is unclear but a key component appears to be DNA methylation
303(2)
X chromosome inactivation in mammals involves very long range cis-acting repression of gene expression
305(1)
The unique organization and expression of Ig and TCR genes
306(9)
DNA rearrangements in B and T cells generate cell-specific exons encoding Ig and TCR variable regions
308(1)
Heavy chain class switching involves joining of a single VDJ exon to alternative constant region transcription units
309(1)
The monospecificity of Igs and TCRs is due to allelic and light chain exclusion
310(5)
Instability of the human genome: mutation and DNA repair
315(36)
An overview of mutation, polymorphism, and DNA repair
316(1)
Simple mutations
316(13)
Mutations due to errors in DNA replication and repair are frequent
316(1)
Classes of genetic polymorphisms and sequence variation
317(1)
The frequency of individual base substitutions is nonrandom according to substitution class
318(1)
The frequency and spectrum of mutations in coding DNA differs from that in noncoding DNA
318(1)
Mechanisms that affect the population frequency of alleles
319(1)
The location of base substitutions in coding DNA is nonrandom
320(1)
Classes of single base substitution in polypeptide-encoding DNA
321(1)
Substitution rates vary considerably between different genes and between different gene components
322(1)
The substitution rate can vary in different chromosomal regions and in different lineages
323(3)
Sex differences in mutation rate and the question of male-driven evolution
326(3)
Genetic mechanisms which result in sequence exchanges between repeats
329(2)
Replication slippage can cause VNTR polymorphism at short tandem repeats (microsatellites)
329(1)
Large units of tandemly repeated DNA are prone to insertion/deletion as a result of unequal crossover or unequal sister chromatid exchanges
329(1)
Gene conversion events may be relatively frequent in tandemly repetitive DNA
329(2)
Pathogenic mutations
331(6)
There is a high deleterious mutation rate in hominids
332(1)
The mitochondrial genome is a hotspot for pathogenic mutations
333(1)
Most splicing mutations alter a conserved sequence needed for normal splicing, but some occur in sequences not normally required for splicing
334(2)
Mutations that introduce a premature termination codon often result in unstable mRNA but other outcomes are possible
336(1)
The pathogenic potential of repeated sequences
337(7)
Slipped strand mispairing of short tandem repeats predisposes to pathogenic deletions and frameshifting insertions
337(1)
Unstable expansion of short tandem repeats can cause a variety of diseases but the mutational mechanism is not well understood
337(2)
Tandemly repeated and clustered gene families may be prone to pathogenic unequal crossover and gene conversion-like events
339(1)
Interspersed repeats often predispose to large deletions and duplications
340(2)
Pathogenic inversions can be produced by intrachromatid recombination between inverted repeats
342(1)
DNA sequence transposition is not uncommon and can cause disease
343(1)
DNA repair
344(7)
DNA repair usually involves cutting out and resynthesizing a whole area of DNA surrounding the damage
345(1)
DNA repair systems share components and processes with the transcription and recombination machinery
345(2)
Hypersensitivity to agents that damage DNA is often the result of an impaired cellular response to DNA damage, rather than defective DNA repair
347(4)
Our place in the tree of life
351(44)
Evolution of gene structure and duplicated genes
352(9)
Spliceosomal introns probably originated from group II introns and first appeared in early eukaryotic cells
352(1)
Complex genes can evolve by intragenic duplication, often as a result of exon duplication
352(1)
Intron groups
353(1)
Exon shuffling can bring together new combinations of protein domains
353(1)
Gene duplication has played a crucially important role in the evolution of multicellular organisms
354(1)
The globin superfamily has evolved by a process of gene duplications, gene conversions, and gene loss/inactivation
354(1)
Symmetrical exons and intron phases
355(2)
Gene duplication mechanisms and paralogy
357(3)
Retrotransposition can permit exon shuffling and is an important contributor to gene evolution
360(1)
Evolution of chromosomes and genomes
361(11)
The mitochondrial genome may have originated following endocytosis of a prokaryotic cell by a eukaryotic cell precursor
361(1)
The universal tree of life and horizontal gene transfer
362(1)
Reduced selection pressure caused the mitochondrial genetic code to diverge
363(1)
The evolution of vertebrate genomes may have involved whole genome duplication
363(1)
There have been numerous major chromosome rearrangements during the evolution of mammalian genomes
364(2)
Segmental duplication in primate lineages and the evolutionary instability of pericentromeric and subtelomeric sequences
366(1)
The human X and Y chromosomes exhibit substantial regions of sequence homology, including common pseudoautosomal regions
367(1)
Human sex chromosomes evolved from autosomes and diverged due to periodic regional suppression of recombination
368(3)
Sex chromosome differentiation results in progressive Y chromosome degeneration and X chromosome inactivation
371(1)
Molecular phylogenetics and comparative genomics
372(5)
Molecular phylogenetics uses sequence alignments to construct evolutionary trees
372(2)
New computer programs align large scale and whole genome sequences, aiding evolutionary analyses and identification of conserved sequenes
374(1)
Gene number is generally proportional to biological complexity
375(1)
The extent of progressive protein specialization is being revealed by proteome comparisons
376(1)
What makes us human?
377(8)
What makes us different from mice?
378(3)
What makes us different from our nearest relatives, the great apes?
381(2)
A glossary of common metazoan phylogenetic groups and terms
383(2)
Evolution of human populations
385(10)
Genetic evidence has suggested a recent origin of modern humans from African populations
385(2)
Human genetic diversity is low and is mostly due to variation within populations rather than between them
387(2)
Coalescence analyses
389(6)
PART THREE: Mapping and identifying disease genes and mutations
395(142)
Genetic mapping of Mendelian characters
397(18)
Recombinants and nonrecombinants
398(4)
The recombination fraction is a measure of genetic distance
398(1)
Recombination fractions do not exceed 0.5 however great the physical distance
398(1)
Mapping functions define the relationship between recombination fraction and genetic distance
399(1)
Chiasma counts and total map length
399(1)
Physical vs. genetic maps: the distribution of recombinants
400(2)
Genetic markers
402(2)
Mapping human disease genes requires genetic markers
402(1)
The heterozygosity or polymorphism information content measure how informative a marker is
402(1)
The development of human genetic markers
403(1)
DNA polymorphisms are the basis of all current genetic markers
403(1)
Informative and uniformative meioses
404(1)
Two-point mapping
404(3)
Scoring recombinants in human pedigrees is not always simple
404(1)
Computerized lod score analysis is the best way to analyze complex pedigrees for linkage between Mendelian characters
405(1)
Calculation of lod scores for the families in Figure 13.6
406(1)
Lod scores of +3 and -2 are the criteria for linkage and exclusion (for a single test)
406(1)
For whole genome searches a genome-wide threshold of significance must be used
406(1)
Multipoint mapping is more efficient than two-point mapping
407(1)
Multipoint linkage can locate a disease locus on a framework of markers
407(1)
Marker framework maps: the CEPH families
407(1)
Bayesian calculation of linkage threshold
407(1)
Multipoint disease-marker mapping
408(1)
Fine-mapping using extended pedigrees and ancestral haplotypes
408(3)
Autozygosity mapping can map recessive conditions efficiently in extended inbred families
408(1)
Identifying shared ancestral segments allowed high-resolution mapping of the loci for cystic fibrosis and Nijmegen breakage syndrome
409(2)
Standard lod score analysis is not without problems
411(4)
Errors in genotyping and misdiagnoses can generate spurious recombinants
411(1)
Computational difficulties limit the pedigrees that can be analyzed
412(1)
Locus heterogeneity is always a pitfall in human gene mapping
413(1)
Meiotic mapping has limited resolution
413(1)
Characters whose inheritance is not Mendelian are not amenable to mapping by the methods described in this chapter
413(2)
Identifying human disease genes
415(20)
Principles and strategies in identifying disease genes
416(1)
Position-independent strategies for identifying disease genes
416(2)
Identifying a disease gene through knowing the protein product
416(2)
Identifying the disease gene through an animal model
418(1)
Identification of a disease gene using position-independent DNA sequence knowledge
418(1)
Positional cloning
418(5)
The first step is to define the candidate region as tightly as possible
419(1)
A contig of clones must be established across the candidate region
419(1)
A transcript map defines all genes within the candidate region
420(1)
Genes from the candidate region must be prioritized for mutation testing
421(1)
Transcript mapping: laboratory methods that supplement database analysis for identifying expressed sequences within genomic clones
421(1)
The special relevance of mouse mutants
422(1)
Use of chromosomal abnormalities
423(5)
Patients with a balanced chromosomal abnormality and an unexplained phenotype are interesting
423(1)
Mapping mouse genes
423(2)
Patients with two Mendelian conditions, or a Mendelian condition plus mental retardation, may have a chromosomal deletion
425(1)
Pointers to the presence of chromosome abnormalities
426(1)
Position effects -- a pitfall in disease gene identification
427(1)
Confirming a candidate gene
428(1)
Mutation screening to confirm a candidate gene
428(1)
CGH for detecting submicroscopic chromosomal imbalances
428(1)
Once a candidate gene is confirmed, the next step is to understand its function
429(1)
Eight examples illustrate various ways disease genes have been identified
429(6)
Direct identification of a gene through a chromosome abnormality: Sotos syndrome
429(1)
Pure transcript mapping: Treacher Collins syndrome
430(1)
Large-scale sequencing and search for homologs: branchio-oto-renal syndrome
430(1)
Positional candidates defined by function: rhodopsin and fibrillin
431(1)
A positional candidate identified through comparison of the human and mouse maps: PAX3 and Waardenburg syndrome
431(1)
Inference from function in vitro: Fanconi anemia
431(1)
Inference from function in vivo: myosin 15 and DFNB3 deafness
431(1)
Inference from the expression pattern: otoferlin
431(4)
Mapping and identifying genes conferring susceptibility to complex diseases
435(26)
Deciding whether a non-Mendelian character is genetic: the role of family, twin and adoption studies
436(1)
The λ value is a measure of familial clustering
436(1)
The importance of shared family environment
436(1)
Twin studies suffer from many limitations
436(1)
Adoption studies: the gold standard for disentangling genetic and environmental factors
437(1)
Segregation analysis allows analysis of characters that are anywhere on the spectrum between purely Mendelian and purely polygenic
437(2)
Bias of ascertainment is often a problem with family data: the example of autosomal recessive conditions
438(1)
Complex segregation analysis is a general method for estimating the most likely mix of genetic factors in pooled family data
438(1)
Linkage analysis of complex characters
439(3)
Standard lod score analysis is usually inappropriate for non-Mendelian characters
439(1)
Correcting the segregation ratio
439(1)
Non-parametric linkage analysis does not require a genetic model
440(1)
Shared segment analysis in families: affected sib pair and affected pedigree member analysis
441(1)
Thresholds of significance are an important consideration in analysis of complex diseases
442(1)
Association studies and linkage disequilibrium
442(5)
Why associations happen
442(1)
Association is in principle quite distinct from linkage, but where the family and the population merge, linkage and association merge
443(1)
Measures of linkage disequilibrium
443(1)
Many studies show islands of linkage disequilibrium separated by recombination hotspots
444(1)
Design of association studies
445(1)
The transmission disequilibrium test (TDT) to determine whether marker allele M1 is associated with a disease
446(1)
Linkage and association: complementary techniques
447(1)
Identifying the susceptibility alleles
447(1)
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)
447(1)
Eight examples illustrate the varying success of genetic dissection of complex diseases
448(9)
Breast cancer: identifying a Mendelian subset has led to important medical advances, but does not explain the causes of the common sporadic disease
448(2)
Hirschsprung disease: an oligogenic disease
450(1)
Alzheimer disease: genetic factors are important both in the common late-onset form and in the rare Mendelian early-onset forms, but they are different genes, acting in different ways
450(1)
Type 1 diabetes mellitus: still the geneticist's nightmare?
451(1)
Alzheimer disease, ApoE testing and discrimination
452(1)
Type 2 diabetes: two susceptibility factors, one so common as to be undetectable by linkage; the other very complex and in certain populations only
453(2)
Inflammatory bowel disease: a clear-cut susceptibility gene identified
455(1)
Schizophrenia: the special problems of psychiatric or behavioral disorders
455(1)
Obesity: genetic analysis of a quantitative trait
456(1)
Overview and summary
457(4)
Why is it so difficult?
457(1)
If it all works out and we identify susceptibility alleles---then what?
457(4)
Molecular pathology
461(26)
Introduction
462(1)
The convenient nomenclature of A and a alleles hides a vast diversity of DNA sequences
462(1)
A first classification of mutations is into loss of function vs. gain of function mutations
462(3)
For molecular pathology, the important thing is not the sequence of a mutant allele but its effect
462(1)
The main classes of mutation
462(1)
Nomenclature for describing sequence changes
463(1)
Loss of function is likely when point mutations in a gene produce the same pathological change as deletions
463(1)
A nomenclature for describing the effect of an allele
463(1)
Gain of function is likely when only a specific mutation in a gene produces a given pathology
464(1)
Deciding whether a DNA sequence change is pathogenic can be difficult
465(1)
Loss of function mutations
465(4)
Many different changes to a gene can cause loss of function
465(1)
Hemoglobinopathies
465(1)
Guidelines for assessing the significance of a DNA sequence change
466(1)
In haploinsufficiency a 50% reduction in the level of gene function causes an abnormal phenotype
467(2)
Mutations in proteins that work as dimers or multimers sometimes produce dominant negative effects
469(1)
Epigenetic modification can abolish gene function even without a DNA sequence change
469(1)
Gain of function mutations
469(2)
Acquisition of a novel function is rare in inherited disease but common in cancer
469(1)
Overexpression may be pathogenic
470(1)
Qualitative changes in a gene product can cause gain of function
471(1)
Molecular pathology: from gene to disease
471(7)
For loss of function mutations the phenotypic effect depends on the residual level of gene function
471(1)
Molecular pathology of Prader-Willi and Angelman syndromes
472(2)
Loss of function and gain of function mutations in the same gene will cause different diseases
474(1)
Variability within families is evidence of modifier genes or chance effects
475(1)
Unstable expanding repeats -- a novel cause of disease
476(2)
Protein aggregation is a common pathogenic mechanism in gain of function diseases
478(1)
For mitochondrial mutations, heteroplasmy and instability complicate the relationship between genotype and phenotype
478(1)
Molecular pathology: from disease to gene
478(2)
The gene underlying a disease may not be the obvious one
479(1)
Locus heterogeneity is the rule rather than the exception
479(1)
Mutations in different members of a gene family can produce a series of related or overlapping syndromes
479(1)
Clinical and molecular classifications are alternative tools for thinking about diseases, and each is valid in its own sphere
480(1)
Molecular pathology of chromosomal disorders
480(7)
Microdeletion syndromes bridge the gap between single gene and chromosomal syndromes
480(3)
The major effects of chromosomal aneuploidies may be caused by dosage imbalances in a few identifiable genes
483(4)
Cancer genetics
487(22)
Introduction
488(1)
The evolution of cancer
488(1)
Oncogenes
489(3)
The history of oncogenes
489(1)
Two ways of making a series of successive mutations more likely
489(1)
The functions of oncogenes
490(1)
Activation of proto-oncogenes
490(2)
Tumor suppressor genes
492(5)
The retinoblastoma paradigm
492(5)
Loss of heterozygosity (LoH) screening is widely used for trying to identify TS gene locations
497(1)
Tumor suppressor genes are often silenced epigenetically by methylation
497(1)
Stability of the genome
497(4)
Chromosomal instability
497(2)
DNA repair defects and DNA-level instability
499(1)
Hereditary nonpolyposis colon cancer and microsatellite instability
499(1)
p53 and apoptosis
500(1)
Control of the cell cycle
501(1)
The G1--S checkpoint
501(1)
Integrating the data: pathways and capabilities
502(2)
Pathways in colorectal cancer
502(1)
A successful tumor must acquire six specific capabilities
503(1)
What use is all this knowledge?
504(5)
Genetic testing in individuals and populations
509(28)
Introduction
510(1)
The choice of material to test: DNA, RNA or protein
510(1)
Scanning a gene for mutations
511(4)
Methods based on sequencing
511(1)
Methods based on detecting mismatches or heteroduplexes
511(1)
Methods based on single-strand conformation analysis
512(1)
Methods based on translation: the protein truncation test
513(1)
Methods for detecting deletions
513(1)
Methods for detecting DNA methylation patterns
514(1)
Testing for a specified sequence change
515(6)
Many simple methods are available for genotyping a specified variant
516(2)
Multiplex amplifiable probe hybridization (MAPH)
518(1)
Methods for high-throughput genotyping
519(1)
Genetic testing for triplet repeat diseases
519(2)
Geographical origin is an important consideration for some tests
521(1)
Gene tracking
521(8)
Gene tracking involves three logical steps
521(3)
Two methods for high-throughput genotyping
524(1)
Recombination sets a fundamental limit on the accuracy of gene tracking
524(1)
Calculating risks in gene tracking
524(3)
The logic of gene tracking
527(1)
The special problems of Duchenne muscular dystrophy
528(1)
Population screening
529(3)
Acceptable screening programs must fit certain criteria
529(1)
Use of Bayes' theorem for combining probabilities
529(1)
Specificity and sensitivity measure the technical performance of a screening test
530(1)
Organization of a genetic screening program
531(1)
DNA profiling can be used for identifying individuals and determining relationships
532(5)
A variety of different DNA polymorphisms have been used for profiling
532(2)
DNA profiling can be used to determine the zygosity of twins
534(1)
DNA profiling can be used to disprove or establish paternity
534(1)
DNA profiling is a powerful tool for forensic investigations
535(1)
The Prosecutor's Fallacy
535(2)
PART FOUR: New horizons: into the 21st century
537(94)
Beyond the genome project: functional genomics, proteomics and bioinformatics
539(36)
An overview of functional genomics
540(1)
The information obtained from the structural phase of the Human Genome Project is of limited use without functional annotation
540(1)
The functions of individual genes can be described at the biochemical, cellular and whole-organism levels
540(1)
Functional relationships among genes must be studied at the levels of the transcriptome and proteome
540(1)
The function of glucokinase
541(1)
High-throughput analysis techniques and bioinformatics are the enabling technologies of functional genomics
541(1)
Functional annotation by sequence comparison
541(4)
Tentative gene functions can be assigned by sequence comparison
541(2)
Consensus search methods can extend the number of homologous relationships identified
543(1)
Similarities and differences between genomes indicate conserved and functionally important sequences
543(1)
Comparative genomics can be exploited to identify and characterize human disease genes
544(1)
A stubborn minority of genes resist functional annotation by homology searching
545(1)
Global mRNA profiling (transcriptomics)
545(8)
Transcriptome analysis reveals how changes in patterns of gene expression coordinate the biochemical activities of the cell in health and disease
545(1)
Direct sequence sampling is a statistical method for determining the relative abundances of different transcripts
546(1)
Sequence sampling techniques for the global analysis of gene expression
547(1)
DNA microarrays use multiplex hybridization assays to measure the abundances of thousands of transcripts simultaneously
548(2)
The analysis of DNA array data involves the creation of a distance matrix and the clustering of related datapoints using reiterative algorithms
550(2)
DNA arrays have been used to study global gene expression in human cell lines, tissue biopsies and animal disease models
552(1)
Proteomics
553(19)
Proteomics encompasses the analysis of protein expression, protein structure and protein interactions
553(1)
Expression proteomics has flourished through the combination of two major technology platforms: two-dimensional gel electrophoresis (2DGE) and mass spectrometry
554(1)
Protein chips
554(3)
Mass spectrometry in proteomics
557(1)
Expression proteomics has been used to study changes in the proteome associated with disease and toxicity
558(1)
Protein structures provide important functional information
559(3)
There are many different ways to study individual protein interactions
562(1)
Determination of protein structures
563(1)
High throughput interaction screening using library-based methods
564(3)
Structural classification of proteins
567(4)
The challenge of interaction proteomics is to assemble a functional interaction map of the cell
571(1)
Information about protein interactions with small ligands can improve our understanding of biomolecular processes and provides a rational basis for the design of drugs
572(1)
Summary
572(3)
Genetic manipulation of cells and animals
575(34)
An overview of gene transfer technology
576(1)
Principles of gene transfer
576(18)
Gene transfer can be used to introduce new, functional DNA sequences into cultured animal cells either transiently or stably
576(1)
The production of transgenic animals requires stable gene transfer to the germ line
577(1)
Methods of gene transfer to animal cells in culture
578(1)
Selectable markers for animal cells
579(3)
Isolation and manipulation of mammalian embryonic stem cells
582(2)
The control of transgene expression is an important consideration in any gene transfer experiment
584(2)
Gene transfer can also be used to produce defined mutations and disrupt the expression of endogenous genes
586(2)
Gene targeting allows the production of animals carrying defined mutations in every cell
588(1)
Site-specific recombination allows conditional gene inactivation and chromosome engineering
589(2)
Transgenic strategies can be used to inhibit endogenous gene function
591(3)
Using gene transfer to study gene expression and function
594(5)
Gene expression and regulation can be investigated using reporter genes
594(1)
Reporter genes for animal cells
595(1)
Gene function can be investigated by generating loss-of-function and gain-of-function mutations and phenocopies
595(2)
The large scale analysis of gene function by insertional mutagenesis and systematic RNA interference are cornerstones of functional genomics
597(2)
Sophisticated vectors used for insertional mutagenesis
599(1)
Creating disease models using gene transfer and gene targeting technology
599(10)
Modeling disease pathogenesis and drug treatment in cell culture
599(1)
It may be difficult to identify animal disease models generated spontaneously or induced by random mutagenesis
600(2)
Mice have been widely used as animal models of human disease largely because specific mutations can be created at a predetermined locus
602(1)
Loss-of-function mutations can be modeled by gene targeting, and gain-of-function mutations by the expression of dominant mutant genes
602(1)
The potential of animals for modeling human disease
603(1)
Increasing attention is being focused on the use of transgenic animals to model complex disorders
604(1)
Mouse models of human disease may be difficult to construct because of a variety of human/mouse differences
605(4)
New approaches to treating disease
609(22)
Treatment of genetic disease is not the same as genetic treatment of disease
610(1)
Treatment of genetic disease
610(1)
Using genetic knowledge to improve existing treatments and develop new versions of conventional treatments
610(6)
Pharmacogenetics promises to increase the effectiveness of drugs and reduce dangerous side effects
610(1)
Drug companies have invested heavily in genomics to try to identify new drug targets
611(1)
Cell-based treatments promise to transform the potential of transplantation
611(2)
Recombinant proteins and vaccines
613(1)
The ethics of human cloning
614(2)
Principles of gene therapy
616(1)
Methods for inserting and expressing a gene in a target cell or tissue
616(8)
Genes can be transferred to the recipient cells in the laboratory (ex vivo) or within the patient's body (in vivo)
616(1)
Constructs may be designed to integrate into the host cell chromosomes or to remain as episomes
616(1)
Germ line versus somatic gene therapy
617(2)
1995 NIH Panel report on gene therapy (Orkin-Motulsky report)
619(1)
Designer babies
619(1)
Viruses are the most commonly used vectors for gene therapy
619(3)
Nonviral vector systems avoid many of the safety problems of recombinant viruses, but gene transfer rates are generally low
622(2)
Methods for repairing or inactivating a pathogenic gene in a cell or tissue
624(1)
Repairing a mutant allele by homologous recombination
624(1)
Inhibition of translation by antisense oligonucleotides
624(1)
Selective destruction or repair of mRNA by a ribozyme
625(1)
Selective inhibition of the mutant allele by RNA interference (RNAi)
625(1)
Some examples of attempts at human gene therapy
625(6)
The first definite success: a cure for X-linked severe combined immunodeficiency
626(1)
Attempts at gene therapy for cystic fibrosis
626(1)
Attempts at gene therapy for Duchenne muscular dystrophy
627(1)
Gene therapy for cancer
628(1)
Gene therapy for infectious disease: HIV
628(3)
Glossary 631(14)
Disease index 645(2)
Index 647

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