Human molecular genetics:
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| Main Authors: | , |
|---|---|
| Format: | Book |
| Language: | English |
| Published: |
London [u.a.]
Garland Science
2004
|
| Edition: | 3. ed. |
| Subjects: | |
| Online Access: | Inhaltsverzeichnis |
| Item Description: | Includes bibliographical references and index |
| Physical Description: | XXV, 674 S. Ill., graph. Darst. |
| ISBN: | 0815341849 0815341822 |
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MARC
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| 100 | 1 | |a Strachan, Tom |d 1952- |e Verfasser |0 (DE-588)11355785X |4 aut | |
| 245 | 1 | 0 | |a Human molecular genetics |c Tom Strachan and Andrew P. Read |
| 246 | 1 | 3 | |a Human molecular genetics 3 |
| 250 | |a 3. ed. | ||
| 264 | 1 | |a London [u.a.] |b Garland Science |c 2004 | |
| 300 | |a XXV, 674 S. |b Ill., graph. Darst. | ||
| 336 | |b txt |2 rdacontent | ||
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| 338 | |b nc |2 rdacarrier | ||
| 500 | |a Includes bibliographical references and index | ||
| 650 | 4 | |a Génétique moléculaire humaine | |
| 650 | 7 | |a Medische genetica |2 gtt | |
| 650 | 7 | |a Moleculaire genetica |2 gtt | |
| 650 | 4 | |a Genome, Human | |
| 650 | 4 | |a Human molecular genetics | |
| 650 | 4 | |a Molecular Biology | |
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Record in the Search Index
| _version_ | 1804130253759578112 |
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| adam_text | Contents
Abbreviations xxiii
Preface xxvii
Supplementary learning aids xxviii
Before we start Intelligent use of the Internet xxix
PART ONE: The Basics 1
Chapter 1 DNA structure and gene expression 3
1.1 Building blocks and chemical bonds in DNA, RNA and polypeptides 4
1.1.1 DNA, RNA and polypeptides are large polymers defined by a linear sequence of simple repeating units 4
1.1.2 Covalent bonds confer stability; weaker noncovalent bonds facilitate interinolecular associations
and stabilize structure r
1.2 DNA structure and replication X
1.2.1 The structure of DNA is an antiparallcl double helix K
Box 1.1 Examples of the importance of hydrogen bonding in nucleic acids and proteins 10
1.2.2 DNA replication is semi conservative and synthesis of DNA strands is semi discontinuous HI
1.2.3. The DNA replication machinery in mammalian cells is complex Id
Box 1.2 Major classes of proteins used in the DNA replication machinery 12
1.2.4 Viral genomes are frequently maintained by RNA replication rather than DNA replication 13
1.3 RNA transcription and gene expression 13
1.3.1 The flow of genetic information in cells is almost exclusively one way: DNA—?RNA—? protein 13
1.3.2 Only a small fraction of the DNA in complex organisms is expressed to give a protein or RNA
product 15
1.3.3 During transcription genetic information in some DNA segments (genes) specifies RNA 16
1.3.4 Cis acting regulatory elements and fraiis acting transcription factors are required in eukaryotic
gene expression 17
1.3.5 Tissue specific gene expression involves selective activation of specific genes 19
1.4 RNA processing 19
1.4.1 RNA splicing removes nonessential RNA sequences from the primary transcript 19
1.4.2 Specialized nucleotides are added to the 5 and 3 ends of most RNA polymerase II transcripts 22
1.5 Translation, post translational processing and protein structure 23
1.5.1 During translation mRNA is decoded on ribosomes to specify the synthesis of polypeptides 23
1.5.2 The genetic code is degenerate and not quite a universal code 25
1.5.3 Post translational modifications include chemical modifications of some amino acids and
polypeptide cleavage 2(
1.5.4 Protein secretion and intracellular export is controlled by specific localization signals or by
chemical modifications 2N
1.5.5 Protein structure is highly varied and not easily predicted from the amino acid sequence 29
Chapter 2 Chromosome structure and function 33
2.1 Ploidy and the cell cycle 34
2.2 Structure and function of chromosomes 34
2.2.1 Packaging of DNA into chromosomes requires multiple hierarchies of DNA folding 35
vi CONTENTS
2.2.2 Individual chromosomes occupy nonoverlapping territories in an interphase nucleus 35
2.2.3 Chromosomes as functioning organelles: the pivotal role of the centromere 36
Box 2.1 The mitotic spindle and its components 37
2.2.4 Chromosomes as functioning organelles: origins ot replication 38
2.2.5 Chromosomes as functioning organelles: the telomeres 39
2.2.6 Heterochromatin and euchromatin 40
2.3 Mitosis and meiosis are the two types of cell division 40
2.3.1 Mitosis is the normal form of cell division 40
2.3.2 Meiosis is a specialized form of cell division giving rise to sperm and egg cells 41
2.3.3 X—Y pairing and the pseudoautosomal regions 44
2.4 Studying human chromosomes 44
2.4.1 Mitotic chromosomes can be seen in any dividing cell, but meiotic chromosomes are hard to study in
humans 44
Box 2.2 Chromosome banding 48
2.4.2 Molecular cytogenetics: chromosome FISH 48
Box 2.3 Human chromosome nomenclature 49
2.4.3 Chromosome painting, molecular karyotyping and comparative genome hybridization 49
2.5 Chromosome abnormalities 51
2.5.1 Types of chromosomal abnormality 51
2.5.2 Numerical chromosomal abnormalities involve gain or loss of complete chromosomes 52
Box 2.4 Nomenclature of chromosome abnormalities 53
2.5.3 Structural chromosomal abnormalities result from misrepair of chromosome breaks or from
malfunction of the recombination system 54
2.5.4 Apparently normal chromosomal complements may be pathogenic if they have the wrong
parental origin 57
Chapter 3 Cells and development 59
3.1 The structure and diversity of cells 60
3.1.1 Prokaryotes and eukaryotes represent the fundamental division of cellular life forms 60
3.1.2 Cell size and shape can vary enormously, but rates of diffusion fix some upper limits 61
3.1.3 In multicellular organisms, there is a fundamental distinction between somatic cells and the germ line 61
Box 3.1 Intracellular organization of animal cells 62
Box 3.2 The cytoskeleton: the key to cell movement and cell shape and a major framework
for intracellular transport 64
3.1.4 In multicellular organisms, no two cells carry exactly the same DNA sequence 64
3.1.5 Cells from multicellular organisms can be studied in situ or in culture 65
3.2 Cell interactions 66
3.2.1 Communication between cells involves the perception of signaling molecules by specific receptors 66
3.2.2 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
3.2.3 The organization of cells to form tissues requires cell adhesion 70
3.2.4 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
3.3 An overview of development 71
3.4 The specialization of cells during development 72
3.4.1. Cell specialization involves an irreversible series of hierarchical decisions 72
Box 3.3 Animal models of development 73
3.4.2 The choice between alternative fates may depend on lineage or position 73
Box 3.4 Twinning in human embryos 74
CONTENTS I vii
3.4.3 Stem cells are self renewing progenitor cells 74
Box 3.5 Where our tissues come from the developmental hierarchy in mammals 75
Box 3.6 The diversity of human cells 76
3.4.4. A variety of tissue stem cells are known to exist but much remains to be learned about them 77
3.4.5. Embryonic stem (ES) cells have the potential to form any tissue 78
3.4.6 The differentiation potential of tissue stem cells is controversial 79
3.5 Pattern formation in development 79
3.5.1 Emergence of the body plan is dependent on axis specification and polarization HO
3.5.2 Homeotic mutations reveal the molecular basis of positional identity 80
3.5.3 Pattern formation often depends on signal gradients 80
3.6 Morphogenesis 81
3.6.1 Morphogenesis can be driven by changes in cell shape and size 81
Box 3.7 Polarizing the mammalian embryo — signals and gene products 82
3.6.2 Major morphogenetic changes in the embryo result from differential cell affinity 82
3.6.3 Cell proliferation and programmed cell death (apoptosis) are important morphogenetic mechanisms 85
3.7 Early human development: fertilization to gastrulation 86
3.7.1 Fertilization activates the egg and brings together the nuclei of sperm and egg to form a unique
individual 86
3.7.2 Cleavage partitions the zygote into many smaller cells 87
3.7.3 Only a small percentage of the cells in the early mammalian embryo gives rise to the mature organism 88
3.7.4 Implantation 88
3.7.5 Gastrulation is a dynamic process whereby cells of the epiblast give rise to the three germ layers 88
Box 3.8 Extra embryonic membranes and the placenta 89
Box 3.9 Sex determination: genes and the environment in development 93
3.8 Neural development 94
3.8.1 The nervous system develops after the ectoderm is induced to differentiate by the underlying
mesoderm 94
3.8.2 Pattern formation in the neural tube involves the coordinated expression of genes along two axes 94
3.8.3 Neuronal differentiation involves the combinatorial activity of transcription factors 95
3.9 Conservation of developmental pathways 97
3.9.1 Many human diseases are caused by the failure of normal developmental processes 97
3.9.2 Developmental processes are highly conserved at both the single gene level and the level of
complete pathways 98
Chapter 4 Genes in pedigrees and populations 101
4.1 Monogenic versus multifactorial inheritance 102
4.2 Mendelian pedigree patterns 102
4.2.1 Dominance and recessiveness are properties of characters, not genes 102
4.2.2 There are five basic Mendelian pedigree patterns 102
Box 4.1 Characteristics of the Mendelian patterns of inheritance 104
4.2.3 The mode of inheritance can rarely be defined unambiguously in a single pedigree 104
4.2.4 One gene—one enzyme does not imply one gene—one syndrome 105
4.2.5 Mitochondrial inheritance gives a recognizable matrilineal pedigree pattern Hid
Box 4.2 The complementation test to discover whether two recessive characters are
determined by allelic genes 106
4.3 Complications to the basic Mendelian pedigree patterns 106
4.3.1 Common recessive conditions can give a pseudo dominant pedigree pattern 106
4.3.2 Failure of a dominant condition to manifest is called nonpenetrance 106
4.3.3 Many conditions show variable expression _ 107
4.3.4 For imprinted genes, expression depends on parental origin 1(19
4.3.5 Male lethality may complicate X linked pedigrees 109
4.3.6 New mutations often complicate pedigree interpretation, and can lead to mosaicism 109
viii I CXINTENTS
4.4 Genetics of multifactorial characters: the polygenic threshold theory 111
4.4.1 Some history 111
4.4.2 Polygenic theory of quantitative traits 112
Box 4.3 Two common misconceptions about regression to the mean 114
Box 4.4 Partitioning of variance 115
4.4.3 Polygenic theory of discontinuous characters 115
4.4.4 Counseling in non Mendelian conditions uses empiric risks 116
4.5 Factors affecting gene frequencies 117
4.5.1 There can be a simple relation between gene frequencies and genotype frequencies 117
4.5.2. Genotype frequencies can be used (with caution) to calculate mutation rates 117
Box 4.5 Hardy Weinberg equilibrium genotype frequencies for allele frequencies
p(Al) and q (A2) 117
Box 4.6 The Hardy Weinberg distribution can be used (with caution) to calculate carrier
frequencies and simple risks for counseling 118
Box 4.7 Mutation selection equilibrium 118
4.5.3 Heterozygote advantage can be much more important than recurrent mutation for determining
the frequency of a recessive disease. 118
Box 4.8 Selection in favor of heterozygotes for CF 119
Chapter 5 Amplifying DNA: PCR and cell based DNA cloning 121
5.1 The importance of DNA cloning 122
5.2 PCR: basic features and applications 123
5.2.1 Principles of basic PCR and reverse transcriptase (RT) PCR 123
Box 5.1 A glossary of PCR methods 124
5.2.2 PCR has two major limitations: short sizes and low yields of products 125
5.2.3 General applications of PCR 127
5.2.4 Some PCR reactions are designed to permit multiple amplification products and to amplify previously
uncharacterized sequences 128
5.3 Principles of cell based DNA cloning 129
5.3.1 An overview of cell based DNA cloning 129
Box 5.2 Restriction endonucleases and modification restriction systems 129
5.3.2 Restriction endonucleases enable the target DNA to be cut into manageable pieces which can
be joined to similarly cut vector molecules 130
5.3.3 Introducing recombinant DNA into recipient cells provides a method for fractionating a complex
starting DNA population 133
5.3.4 DNA libraries are a comprehensive set of DNA clones representing a complex starting DNA
population 133
5.3.5 Recombinant screening is often achieved by insertional inactivation of a marker gene 135
Box 5.3 Nonsense suppressor mutations 13°
Box 5.4 The importance of sequence tagged sites (STSs) 13°
5.4 Cloning systems for amplifying different sized fragments 138
5.4.1 Standard plasmid vectors provide a simple way of cloning small DNA fragments in bacterial (and
simple eukaryotic) cells 39
5.4.2 Lambda and cosmid vectors provide an efficient means of cloning moderately large DNA
fragments in bacterial cells 14
5.4.3 Large DNA fragments can be cloned in bacterial cells using vectors based on bacteriophage PI
and F factor plasmids 142
5.4.4 Yeast artificial chromosomes (YACs) enable cloning of megabase fragments 143
5.5 Cloning systems for producing single stranded and mutagenized DNA 14*
CONTI NTS ix
5.5.1 Single stranded DNA for use in DNA sequencing is obtained using M13 or phagemid vectors or
by linear PCR amplification 144
5.5.2 Oligonucleotide mismatch mutagenesis can create a predetermined single nucleotide change in
any cloned gene 146
5.5.3 PCR based mutagenesis includes coupling of desired sequences or chemical groups to a target
sequence and site specific mutagenesis 146
5.6 Cloning systems designed to express genes 147
5.6.1 Large amounts of protein can be produced by expression cloning in bacterial cells 147
5.6.2 Phage display is a form of expression cloning in which proteins are expressed on bacterial cell surfaces 150
5.6.3 Eukaryotic gene expression is carried out with greater fidelity in eukaryotic cell lines 150
Box 5.5 Transferring genes into cultured animal cells 152
Chapter 6 Nucleic acid hybridization: principles and applications 155
6.1 Preparation of nucleic acid probes 156
6.1.1 Nucleic acids can conveniently be labeled in vitro by incorporation of modified nucleotides 156
6.1.2 Nucleic acids can be labeled by isotopic and nonisotopic methods 157
Box 6.1 Principles of autoradiography 159
6.2 Principles of nucleic acid hybridization 161
6.2.1 Nucleic acid hybridization is a method for identifying closely related molecules within two nucleic acid
populations 161
Box 6.2 Fluorescence labeling and detection systems 164
6.2.2 The kinetics of DNA reassociation are defined by the product of DNA concentration and time (C() ) 164
Box 6.3 A glossary of nucleic acid hybridization 166
6.2.3 A wide variety of nucleic acid hybridization assays can be used 167
6.3 Nucleic acid hybridization assays using cloned DNA probes to screen uncloned nucleic
acid populations 168
6.3.1 Dot blot hybridization, a rapid screening method, often employs allele specific oligonucleotide probes 168
Box 6.4 Standard and reverse nucleic acid hybridization assays 169
6.3.2 Southern and Northern blot hybridizations detect nucleic acids that have been size fractionated by gel
electrophoresis 169
6.3.3 Pulsed field gel electrophoresis extends Southern hybridization to include detection of very large
DNA molecules 171
6.3.4 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
6.4 Hybridization assays using cloned target DNA and microarrays 174
6.4.1 Colony blot and plaque lift hybridization are methods for screening separated bacterial colonies
or plaques 174
6.4.2 Gridded high density arrays of transformed cell clones or DNA clones has greatly increased the
efficiency of DNA library screening 175
6.4.3 DNA microarray technology has enormously extended the power of nucleic acid hybridization 175
Chapter 7 Analyzing DNA and gene structure, variation and expression 181
7.1 Sequencing and genotyping DNA 182
7.1.1 Standard DNA sequencing involves enzymatic DNA synthesis using base specific dideoxynucleotide
chain terminators 182
Box 7.1 Producing single stranded DNA sequencing templates 182
7.1.2 Automated DNA sequencing and microarray based re sequencing 183
7.1.3 Basic genotyping of restriction site polymorphisms and variable number of tandem repeat
polymorphisms 183
7.2 Identifying genes in cloned DNA and establishing their structure 186
I
xii | CONTENTS
Chapter 10 Human gene expression 275
10.1 An overview of gene expression in human cells 276
Box 10.1 Spatial and temporal restriction of gene expression in mammalian cells 276
10.2 Control of gene expression by binding of trans acting protein factors to cis acting regulatory
sequences in DNA and RNA 277
10.2.1 Histone modification and chromatin remodeling facilitate access to chromatin by DNA binding factors 278
10.2.2 Ubiquitous transcription factors are required for transcription by RNA polymerases I and III 279
10.2.3 Transcription by RNA polymerase II requires complex sets of ris acting regulatory sequences and
tissue specific transcription factors 280
10.2.4. Transcription factors contain conserved structural motifs that permit DNA binding 282
Box 10.2 Classes of as acting sequence elements involved in regulating transcription of
polypeptide encoding genes 283
10.2.5 A variety of mechanisms permit transcriptional regulation of gene expression in response to
external stimuli 285
10.2.6 Translational control of gene expression can involve recognition of UTR regulatory sequences by
RNA binding proteins 288
10.3 Alternative transcription and processing of individual genes 291
10.3.1 The use of alternative promoters can generate tissue specific isoforms 291
10.3.2 Human genes are prone to alternative splicing and alternative polyadenylation 292
10.3.3 RNA editing is a rare form of processing whereby base specific changes are introduced into RNA 293
Box 10.3 Alternative splicing can alter the functional properties of a protein 293
10.4 Differential gene expression: origins through asymmetry and perpetuation through
epigenetic mechanisms such as DNA methylation 294
10.4.1 Selective gene expression in cells of mammalian embryos most likely develops in response to short
range cell cell signaling events 295
10.4.2 DNA methylation is an important epigenetic factor in perpetuating gene repression in vertebrate cells 295
10.4.3 Animal DNA methylation may provide defense against transposons as well as regulating gene
expression 297
10.5 Long range control of gene expression and imprinting 298
10.5.1 Chromatin structure may exert long range control over gene expression 298
10.5.2 Expression of individual genes in gene clusters may be co ordinated by a common locus control region 299
10.5.3 Some human genes show selective expression of only one of the two parental alleles 300
10.5.4 Genomic imprinting involves differences in the expression of alleles according to parent of origin 301
Box 10.4 Mechanisms resulting in monoallelic expression from biallelic genes in human cells 302
Box 10.5 The nonequivalence of the maternal and paternal genomes 302
10.5.5 The mechanism of genomic imprinting is unclear but a key component appears to be DNA
methylation 303
10.5.6 X chromosome inactivation in mammals involves very long range as acting repression of gene
expression 305
10.6 The unique organization and expression of Ig and TGR genes 306
10.6.1 DNA rearrangements in B andT cells generate cell specific exons encoding Ig and TCR variable
regions 308
10.6.2 Heavy chain class switching involves joining of a single VDJ exon to alternative constant region
transcription units 309
10.6.3 The monospecificity of Igs andTCRs is due to allelic and light chain exclusion 310
Chapter 11 Instability of the human genome: mutation and DNA repair 315
11.1 An overview of mutation, polymorphism, and DNA repair 316
11.2 Simple mutations 316
11.2.1 Mutations due to errors in DNA replication and repair are frequent 316
Box 11.1 Classes of genetic polymorphisms and sequence variation 317
CONTENTS xiii
11.2.2 The frequency of individual base substitutions is nonrandom according to substitution class 318
11.2.3 The frequency and spectrum of mutations in coding DNA differs from that in noncoding DNA 318
Box 11.2 Mechanisms that affect the population frequency of alleles 319
11.2.4 The location of base substitutions in coding DNA is nonrandom 320
Box 11.3 Classes of single base substitution in polypeptide encoding DNA 321
11.2.5 Substitution rates vary considerably between different genes and between different gene components 322
11.2.6 The substitution rate can vary in different chromosomal regions and in different lineages 323
Box 11.4 Sex differences in mutation rate and the question of male driven evolution 326
11.3 Genetic mechanisms which result in sequence exchanges between repeats 329
11.3.1 Replication slippage can cause VNTR polymorphism at short tandem repeats (microsatellites) 329
11.3.2 Large units of tandemly repeated DNA are prone to insertion/deletion as a result of unequal
crossover or unequal sister chromatid exchanges 329
11.3.3 Gene conversion events may be relatively frequent in tandemly repetitive DNA 329
11.4 Pathogenic mutations 331
11.4.1 There is a high deleterious mutation rate in hominids 332
11.4.2 The mitochondrial genome is a hotspot for pathogenic mutations 333
11.4.3 Most splicing mutations alter a conserved sequence needed for normal splicing, but some occur
in sequences not normally required for splicing 334
11.4.4 Mutations that introduce a premature termination codon often result in unstable mRNA but
other outcomes are possible 336
11.5 The pathogenic potential of repeated sequences 337
11.5.1 Slipped strand mispairing of short tandem repeats predisposes to pathogenic deletions and
frameshifting insertions 337
11.5.2 Unstable expansion of short tandem repeats can cause a variety of diseases but the nuitation.il
mechanism is not well understood 337
11.5.3 Tandemly repeated and clustered gene families may be prone to pathogenic unequal crossover and
gene conversion like events 339
11.5.4 Interspersed repeats often predispose to large deletions and duplications 34(1
11.5.5 Pathogenic inversions can be produced by intrachromatid recombination between inverted repeats 342
11.5.6 DNA sequence transposition is not uncommon and can cause disease 343
11.6 DNA repair 344
11.6.1 DNA repair usually involves cutting out and resynthesizing a whole area of DNA surrounding the
damage 345
11.6.2 DNA repair systems share components and processes with the transcription and recombination
machinery 345
11.6.3 Hypersensitivity to agents that damage DNA is often the result of an impaired cellular response
to DNA damage, rather than defective DNA repair 347
Chapter 12 Our place in the tree of life 351
12.1 Evolution of gene structure and duplicated genes 352
12.1.1 Spliceosomal introns probably originated from group II introns and first appeared in early eukaryotic
cells 352
12.1.2 Complex genes can evolve by intragenic duplication, often as a result of exon duplication 352
Box 12.1 Intron groups 353
12.1.3 Exon shuffling can bring together new combinations of protein domains 353
12.1.4 Gene duplication has played a crucially important role in the evolution of multicellular organisms 354
12.1.5 The globin superfamily has evolved by a process of gene duplications, gene conversions, and gene
loss/inactivation 354
Box 12.2 Symmetrical exons and intron phases 355
Box 12.3 Gene duplication mechanisms and paralogy 357
12.1.6 Retrotransposition can permit exon shuffling and is an important contributor to gene evolution 360
xiv CONTENTS
12.2 Evolution of chromosomes and genomes 361
12.2.1 The mitochondrial genome may have originated following endocytosis of a prokaryotic cell by a
eukaryotic cell precursor 361
Box 12.4 The universal tree of life and horizontal gene transfer 362
12.2.2 Reduced selection pressure caused the mitochondrial genetic code to diverge 363
12.2.3 The evolution of vertebrate genomes may have involved whole genome duplication 363
12.2.4 There have been numerous major chromosome rearrangements during the evolution of mammalian
genomes 364
12.2.5 Segmental duplication in primate lineages and the evolutionary instability of pericentromeric and
subtelomeric sequences 366
12.2.6 The human X andY chromosomes exhibit substantial regions of sequence homology, including
common pseudoautosomal regions 367
12.2.7 Human sex chromosomes evolved from autosomes and diverged due to periodic regional
suppression of recombination 368
12.2.8 Sex chromosome differentiation results in progressive Y chromosome degeneration and X
chromosome inactivation 371
12.3 Molecular phylogenetics and comparative genomics 372
12.3.1 Molecular phylogenetics uses sequence alignments to construct evolutionary trees 372
12.3.2 New computer programs align large scale and whole genome sequences, aiding evolutionary analyses
and identification of conserved sequences 374
12.3.3 Gene number is generally proportional to biological complexity 375
12.3.4 The extent of progressive protein specialization is being revealed by proteome comparisons 376
12.4 What makes us human? 377
12.4.1 What makes us different from mice? 378
12.4.2 What makes us different from our nearest relatives, the great apes? 381
Box 12.5 A glossary of common metazoan phylogenetic groups and terms 383
12.5 Evolution of human populations 385
12.5.1 Genetic evidence has suggested a recent origin of modern humans from African populations 385
12.5.2 Human genetic diversity is low and is mostly due to variation within populations rather than
between them 387
Box 12.6 Coalescence analyses 389
PART THREE: Mapping and identifying disease genes and mutations 395
Chapter 13 Genetic mapping of Mendelian characters 397
13.1 Recombinants and nonrecombinants 398
13.1.1 The recombination fraction is a measure of genetic distance 398
13.1.2 Recombination fractions do not exceed 0.5 however great the physical distance 398
13.1.3 Mapping functions define the relationship between recombination fraction and genetic distance 399
13.1.4 Chiasma counts and total map length 399
13.1.5 Physical vs. genetic maps: the distribution of recombinants 400
13.2 Genetic markers 402
13.2.1 Mapping human disease genes requires genetic markers 402
13.2.2 The heterozygosity or polymorphism information content measure how informative a marker is 402
Box 13.1 The development of human genetic markers 403
13.2.3. DNA polymorphisms are the basis of all current genetic markers 403
Box 13.2 Informative and uninformative meioses 404
13.3 Two point mapping 404
13.3.1 Scoring recombinants in human pedigrees is not always simple 404
13.3.2 Computerized lod score analysis is the best way to analyze complex pedigrees for linkage
between Mendelian characters 405
Box 13.3 Calculation of lod scores for the families in Figure 13.6 406
CONTENTS xv
13.3 3 Lod scores of+3 and —2 are the criteria for linkage and exclusion (for a single test) 406
13.3.4 For whole genome searches a genome wide threshold of significance must be used 406
13.4 Multipoint mapping is more efficient than two point mapping 407
13.4.1 Multipoint linkage can locate a disease locus on a framework of markers 407
13.4.2 Marker framework maps: the CEPH families 407
Box 13.4 Bayesian calculation of linkage threshold 407
13.4.3 Multipoint disease marker mapping 408
13.5 Fine mapping using extended pedigrees and ancestral haplotypes 408
13.5.1 Autozygosity mapping can map recessive conditions efficiently in extended inbred families 408
13.5.2 Identifying shared ancestral segments allowed high resolution mapping of the loci for cystic
fibrosis and Nijmegen breakage syndrome 409
13.6 Standard lod score analysis is not without problems 411
13.6.1 Errors in genotyping and misdiagnoses can generate spurious recombinants 411
13.6.2 Computational difficulties limit the pedigrees that can be analyzed 412
13.6.3 Locus heterogeneity is always a pitfall in human gene mapping 413
13.6.4 Meiotic mapping has limited resolution 413
13.6.5 Characters whose inheritance is not Mendelian are not amenable to mapping by the methods
described in this chapter 413
Chapter 14 Identifying human disease genes 415
14.1 Principles and strategies in identifying disease genes 416
14.2 Position independent strategies for identifying disease genes 416
14.2.1 Identifying a disease gene through knowing the protein product 416
14.2.2 Identifying the disease gene through an animal model 418
14.2.3 Identification of a disease gene using position independent DNA sequence knowledge 418
14.3 Positional cloning 418
14.3.1 The first step is to define the candidate region as tightly as possible 419
14.3.2 A contig of clones must be established across the candidate region 419
14.3.3 A transcript map defines all genes within the candidate region 420
14.3.4 Genes from the candidate region must be prioritized for mutation testing 421
Box 14.1 Transcript mapping: laboratory methods that supplement database analysis for
identifying expressed sequences within genomic clones 421
14.3.5 The special relevance of mouse mutants 422
14.4 Use of chromosomal abnormalities 423
14.4.1 Patients with a balanced chromosomal abnormality and an unexplained phenotype are interesting 423
Box 14.2 Mapping mouse genes 423
14.4.2 Patients with two Mendelian conditions, or a Mendelian condition plus mental retardation, may have a
chromosomal deletion 425
Box 14.3 Pointers to the presence of chromosome abnormalities 426
Box 14.4 Position effects — a pitfall in disease gene identification 427
14.5 Confirming a candidate gene 428
14.5.1 Mutation screening to confirm a candidate gene 428
Box 14.5 CGH for detecting submicroscopic chromosomal imbalances 428
14.5.2 Once a candidate gene is confirmed, the next step is to understand its function 429
14.6 Eight examples illustrate various ways disease genes have been identified 429
14.6.1 Direct identification of a gene through a chromosome abnormality: Sotos syndrome 429
14.6.2 Pure transcript mapping: Treacher Collins syndrome 430
14.6.3 Large scale sequencing and search for homologs: branchio oto renal syndrome 430
14.6.4 Positional candidates defined by function: rhodopsin and fibrillin 431
14.6.5 A positional candidate identified through comparison of the human and mouse maps: PAX3
and Waardenburg syndrome 431
xvi CONTENTS
14.6.6 Inference from function in vitro: Fanconi anemia 431
14.6.7 Inference from function in vivo: myosin 15 and DFNB3 deafness 431
14.6.8 Inference from the expression pattern: otoferlin 431
Chapter 15 Mapping and identifying genes conferring susceptibility to complex diseases 435
15.1 Deciding whether a non Mendelian character is genetic: the role of family, twin and
adoption studies 436
15.1.1 The value is a measure of familial clustering 436
15.1.2 The importance of shared family environment 436
15.1.3 Twin studies suffer from many limitations 436
15.1.4 Adoption studies: the gold standard for disentangling genetic and environmental factors 437
15.2 Segregation analysis allows analysis of characters that are anywhere on the spectrum
between purely Mendelian and purely polygenic 437
15.2.1 Bias of ascertainment is often a problem with family data: the example of autosomal recessive
conditions 438
15.2.2 Complex segregation analysis is a general method for estimating the most likely mix of genetic
factors in pooled family data 438
15.3 Linkage analysis of complex characters 439
15.3.1 Standard lod score analysis is usually inappropriate for non Mendelian characters 439
Box 15.1 Correcting the segregation ratio 439
15.3.2 Non parametric linkage analysis does not require a genetic model 440
15.3.3 Shared segment analysis in families: affected sib pair and affected pedigree member analysis 441
15.3.4 Thresholds of significance are an important consideration in analysis of complex diseases 442
15.4 Association studies and linkage disequilibrium 442
15.4.1 Why associations happen 442
15.4.2 Association is in principle quite distinct from linkage, but where the family and the population
merge, linkage and association merge 443
Box 15.2 Measures of linkage disequilibrium 443
15.4.3 Many studies show islands of linkage disequilibrium separated by recombination hotspots 444
15.4.4 Design of association studies 445
Box 15.3 The transmission disequilibrium test (TDT) to determine whether marker allele
Mj is associated with a disease 446
15.4.5 Linkage and association: complementary techniques 447
15.5 Identifying the susceptibility alleles 447
Box 15.4 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
15.6 Eight examples illustrate the varying success of genetic dissection of complex diseases 448
15.6.1 Breast cancer: identifying a Mendelian subset has led to important medical advances, but does not
explain the causes of the common sporadic disease 448
15.6.2 Hirschsprung disease: an oligogenic disease 450
15.6.3 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
15.6.4 Type 1 diabetes mellitus: still the geneticists nightmare? 451
Ethics Box 1 Alzheimer disease, ApoE testing and discrimination 452
15.6.5 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
15.6.6 Inflammatory bowel disease: a clear cut susceptibility gene identified 455
15.6.7 Schizophrenia: the special problems of psychiatric or behavioral disorders 455
15.6.8 Obesity: genetic analysis of a quantitative trait 456
15.7 Overview and summary 457
15.7.1 Why is it so difficult? 457
15.7.2 If it all works out and we identify susceptibility alleles—then what? 457
CONTENTS xvii
Chapter 16 Molecular pathology 461
16.1 Introduction 462
16.2 The convenient nomenclature of A and a alleles hides a vast diversity of DNA sequences 462
16.3 A first classification of mutations is into loss of function vs. gain of function mutations 462
16.3.1 For molecular pathology, the important thing is not the sequence of a mutant allele but its effect 462
Box 16.1 The main classes of mutation 462
Box 16.2 Nomenclature for describing sequence changes 463
16.3.2 Loss of function is likely when point mutations in a gene produce the same pathological change
as deletions 463
Box 16.3 A nomenclature for describing the effect of an allele 463
16.3.3 Gain of function is likely when only a specific mutation in a gene produces a given pathology 464
16.3.4 Deciding whether a DNA sequence change is pathogenic can be difficult 465
16.4 Loss of function mutations 465
16.4.1 Many different changes to a gene can cause loss of function 465
Box 16.4 Hemoglobinopathies 465
Box 16.5 Guidelines for assessing the significance of a DNA sequence change 466
16.4.2 In haploinsufficiency a 50% reduction in the level of gene function causes an abnormal phenotype 467
16.4.3 Mutations in proteins that work as dimers or multimers sometimes produce dominant negative
effects 469
16.4.4 Epigenetic modification can abolish gene function even without a DNA sequence change 469
16.5 Gain of function mutations 469
16.5.1 Acquisition of a novel function is rare in inherited disease but common in cancer 46V
16.5.2 Overexpression may be pathogenic 470
16.5.3 Qualitative changes in a gene product can cause gain of function 471
16.6 Molecular pathology: from gene to disease 471
16.6.1 For loss of function mutations the phenotypic effect depends on the residual level of gene function 471
Box 16.6 Molecular pathology of Prader Willi and Angelman syndromes 472
16.6.2 Loss of function and gain of function mutations in the same gene will cause different diseases 474
16.6.3 Variability within families is evidence of modifier genes or chance effects 475
16.6.4 Unstable expanding repeats — a novel cause of disease 476
16.6.5 Protein aggregation is a common pathogenic mechanism in gain of function diseases 478
16.6.6 For mitochondrial mutations, heteroplasmy and instability complicate the relationship between
genotype and phenotype 478
16.7 Molecular pathology: from disease to gene 478
16.7.1 The gene underlying a disease may not be the obvious one 479
16.7.2 Locus heterogeneity is the rule rather than the exception 479
16.7.3 Mutations in different members of a gene family can produce a series of related or overlapping
syndromes 479
16.7.4 Clinical and molecular classifications are alternative tools for thinking about diseases, and each is
valid in its own sphere 480
16.8 Molecular pathology of chromosomal disorders 480
16.8.1 Microdeletion syndromes bridge the gap between single gene and chromosomal syndromes 480
16.8.2 The major effects of chromosomal aneuploidies may be caused by dosage imbalances in a tew
identifiable genes 483
Chapter 17 Cancer genetics 487
17.1 Introduction 488
17.2 The evolution of cancer 488
17.3 Oncogenes 489
17.3.1 The history of oncogenes 489
xviii CONTENTS
Box 17.1 Two ways of making a series of successive mutations more likely 489
17.3.2 The functions of oncogenes . 490
17.3.3 Activation of proto oncogenes 490
17.4 Tumor suppressor genes 492
17.4.1 The retinoblastoma paradigm 492
17.4.2 Loss of heterozygosity (LoH) screening is widely used for trying to identify TS gene locations 497
17.4.3 Tumor suppressor genes are often silenced epigenetically by methylation 497
17.5 Stability of the genome 497
17.5.1 Chromosomal instability 497
17.5.2 DNA repair defects and DNA level instability 499
17.5.3 Hereditary nonpolyposis colon cancer and microsatellite instability 499
17.5.4 p53 and apoptosis 500
17.6 Control of the cell cycle 501
17.6.1 The Gl S checkpoint 501
17.7 Integrating the data: pathways and capabilities 502
17.7.1 Pathways in colorectal cancer 502
17.7.2 A successful tumor must acquire six specific capabilities 503
17.8 What use is all this knowledge? 504
Chapter 18 Genetic testing in individuals and populations 509
18.1 Introduction 510
18.2 The choice of material to test: DNA, RNA or protein 510
18.3 Scanning a gene for mutations 511
18.3.1 Methods based on sequencing 511
18.3.2 Methods based on detecting mismatches or heteroduplexes 511
18.3.3 Methods based on single strand conformation analysis 512
18.3.4 Methods based on translation: the protein truncation test 513
18.3.5 Methods for detecting deletions 513
18.3.6 Methods for detecting DNA methylation patterns 514
18.4 Testing for a specified sequence change 515
18.4.1 Many simple methods are available for genotyping a specified variant 516
Box 18.1 Multiplex amplifiable probe hybridization (MAPH) 518
18.4.2 Methods for high throughput genotyping 519
18.4.3 Genetic testing for triplet repeat diseases 519
18.4.4. Geographical origin is an important consideration for some tests 521
18.5 Gene tracking 521
18.5.1 Gene tracking involves three logical steps 521
Box 8.2 Two methods for high throughput genotyping 524
18.5.2 Recombination sets a fundamental limit on the accuracy of gene tracking 524
18.5.3 Calculating risks in gene tracking 524
Box 18.3 The logic of gene tracking 527
18.5.4 The special problems of Duchenne muscular dystrophy 528
18.6 Population screening 529
18.6.1 Acceptable screening programs must fit certain criteria 529
Box 18.4 Use of Bayes theorem for combining probabilities 529
18.6.2 Specificity and sensitivity measure the technical performance of a screening test 530
18.6.3 Organization of a genetic screening program 531
18.7 DNA profiling can be used for identifying individuals and determining relationships 532
18.7.1 A variety of different DNA polymorphisms have been used for profiling 532
18.7.2 DNA profiling can be used to determine the zygosity of twins 534
18.7.3 DNA profiling can be used to disprove or establish paternity 534
CONTENTS xix
18.7.4 DNA profiling is a powerful tool for forensic investigations 535
Box 18.5 The Prosecutor s Fallacy 535
PART FOUR: New horizons: into the 21st century 537
Chapter 19 Beyond the genome project: functional genomics, proteomics and bioinformatics 539
19.1 An overview of functional genomics 540
19.1.1 The information obtained from the structural phase of the Human Genome Project is of limited
use without functional annotation 540
19.1.2 The functions of individual genes can be described at the biochemical, cellular and whole organism
levels 540
19.1.3 Functional relationships among genes must be studied at the levels of the transcriptome and
proteome 540
Box 19.1 The function of glucokinase 541
19.1.4 High throughput analysis techniques and bioinformatics are the enabling technologies of
functional genomics 541
19.2 Functional annotation by sequence comparison 541
19.2.1 Tentative gene functions can be assigned by sequence comparison 541
19.2.2 Consensus search methods can extend the number of homologous relationships identified 543
19.2.3 Similarities and differences between genomes indicate conserved and functionally important sequences 543
19.2.4 Comparative genomics can be exploited to identify and characterize human disease genes 544
19.2.5 A stubborn minority of genes resist functional annotation by homology searching 545
19.3 Global mRNA profiling (transcriptomics) 545
19.3.1 Transcriptome analysis reveals how changes in patterns of gene expression coordinate the biochemical
activities of the cell in health and disease 545
19.3.2 Direct sequence sampling is a statistical method for determining the relative abundances of
different transcripts 546
Box 19.2 Sequence sampling techniques for the global analysis of gene expression 547
19.3.3 DNA microarrays use multiplex hybridization assays to measure the abundances of thousands of
transcripts simultaneously 548
19.3.4 The analysis of DNA array data involves the creation of a distance matrix and the clustering of related
datapoints using reiterative algorithms 550
19.3.5 DNA arrays have been used to study global gene expression in human cell lines, tissue biopsies and
animal disease models 552
19.4 Proteomics 553
19.4.1 Proteomics encompasses the analysis of protein expression, protein structure and protein interactions 553
19.4.2 Expression proteomics has flourished through the combination of two major technology platforms: two
dimensional gel electrophoresis (2DGE) and mass spectrometry 554
Box 19.3 Protein chips 554
Box 19.4 Mass spectrometry in proteomics 557
19.4.3 Expression proteomics has been used to study changes in the proteome associated with disease
and toxicity 558
19.4.4 Protein structures provide important functional information 559
19.4.5. There are many different ways to study individual protein interactions 562
Box 19.5 Determination of protein structures 563
19.4.6. High throughput interaction screening using library based methods 564
Box 19.6 Structural classification of proteins 567
19.4.7 The challenge of interaction proteomics is to assemble a functional interaction map of the cell 571
19.4.8 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
19.5 Summary 572
xx I CONTENTS
Chapter 20 Genetic manipulation of cells and animals 575
20.1 An overview of gene transfer technology 576
20.2 Principles of gene transfer 576
20.2.1 Gene transfer can be used to introduce new, functional DNA sequences into cultured animal
cells either transiently or stably 576
20.2.2 The production of transgenic animals requires stable gene transfer to the germ line 577
Box 20.1 Methods of gene transfer to animal cells in culture 578
Box 20.2 Selectable markers for animal cells 579
Box 20.3 Isolation and manipulation of mammalian embryonic stem cells 582
20.2.3 The control of transgene expression is an important consideration in any gene transfer experiment 584
20.2.4 Gene transfer can also be used to produce defined mutations and disrupt the expression of
endogenous genes 586
20.2.5 Gene targeting allows the production of animals carrying defined mutations in every cell 588
20.2.6 Site specific recombination allows conditional gene inactivation and chromosome engineering 589
20.2.7 Transgenic strategies can be used to inhibit endogenous gene function 591
20.3 Using gene transfer to study gene expression and function 594
20.3.1 Gene expression and regulation can be investigated using reporter genes 594
Box 20.4 Reporter genes for animal cells 595
20.3.2 Gene function can be investigated by generating loss of function and gain of function mutations and
phenocopies 595
20.3.3 The large scale analysis of gene function by insertional mutagenesis and systematic RNA interference
are cornerstones of functional genomics 597
Box 20.5 Sophisticated vectors used for insertional mutagenesis 599
20.4 Creating disease models using gene transfer and gene targeting technology 599
20.4.1 Modeling disease pathogenesis and drug treatment in cell culture 599
20.4.2 It may be difficult to identify animal disease models generated spontaneously or induced by random
mutagenesis 600
20.4.3 Mice have been widely used as animal models of human disease largely because specific mutations can be
created at a predetermined locus 602
20.4.4 Loss of function mutations can be modeled by gene targeting, and gain of function mutations by the
expression of dominant mutant genes 602
Box 20.6 The potential of animals for modeling human disease 603
20.4.5 Increasing attention is being focused on the use of transgenic animals to model complex disorders 604
20.4.6 Mouse models of human disease may be difficult to construct because of a variety of human/mouse
differences 605
Chapter 21 New approaches to treating disease 609
21.1 Treatment of genetic disease is not the same as genetic treatment of disease 610
21.2 Treatment of genetic disease 610
21.3 Using genetic knowledge to improve existing treatments and develop new versions of
conventional treatments 610
21.3.1 Pharmacogenetics promises to increase the effectiveness of drugs and reduce dangerous side effects 610
21.3.2 Drug companies have invested heavily in genomics to try to identify new drug targets 611
21.3.3 Cell based treatments promise to transform the potential of transplantation 611
21.3.4 Recombinant proteins and vaccines 613
Ethics Box 1 The ethics of human cloning 614
21.4 Principles of gene therapy 616
21.5 Methods for inserting and expressing a gene in a target cell or tissue 616
21.5.1 Genes can be transferred to the recipient cells in the laboratory {ex vivo) or within the patient s
body {in vivo) 616
CONTENTS xxi
21.5.2 Constructs may be designed to integrate into the host cell chromosomes or to remain as episomes 616
Ethics Box 2 Germ line versus somatic gene therapy 617
Box 21.1 1995 NIH Panel report on gene therapy (Orkin Motulsky report) 619
Ethics Box 3 Designer babies 619
21.5.3 Viruses are the most commonly used vectors for gene therapy 619
21.5.4 Nonviral vector systems avoid many of the safety problems of recombinant viruses, but gene transfer
rates are generally low 622
21.6 Methods for repairing or inactivating a pathogenic gene in a cell or tissue 624
21.6.1 Repairing a mutant allele by homologous recombination 624
21.6.2 Inhibition of translation by antisense oligonucleotides 624
21.6.3 Selective destruction or repair of mRNA by a ribozyme 625
21.6.4 Selective inhibition of the mutant allele by RNA interference (RNAi) 625
21.7 Some examples of attempts at human gene therapy 625
21.7.1 The first definite success: a cure for X linked severe combined immunodeficiency 626
21.7.2 Attempts at gene therapy for cystic fibrosis 626
21.7.3 Attempts at gene therapy for Duchenne muscular dystrophy 627
21.7.4 Gene therapy for cancer 628
21.7.5 Gene therapy for infectious disease: HIV 628
Glossary 631
Disease index 645
Index 647
|
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| author | Strachan, Tom 1952- Read, Andrew P. 1939- |
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| dewey-tens | 610 - Medicine and health |
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| spelling | Strachan, Tom 1952- Verfasser (DE-588)11355785X aut Human molecular genetics Tom Strachan and Andrew P. Read Human molecular genetics 3 3. ed. London [u.a.] Garland Science 2004 XXV, 674 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Includes bibliographical references and index Génétique moléculaire humaine Medische genetica gtt Moleculaire genetica gtt Genome, Human Human molecular genetics Molecular Biology Molekulargenetik (DE-588)4039987-4 gnd rswk-swf Humangenetik (DE-588)4072653-8 gnd rswk-swf 1\p (DE-588)4123623-3 Lehrbuch gnd-content Molekulargenetik (DE-588)4039987-4 s Humangenetik (DE-588)4072653-8 s DE-604 Read, Andrew P. 1939- Verfasser (DE-588)114651604 aut HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=010510594&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis 1\p cgwrk 20201028 DE-101 https://d-nb.info/provenance/plan#cgwrk |
| spellingShingle | Strachan, Tom 1952- Read, Andrew P. 1939- Human molecular genetics Génétique moléculaire humaine Medische genetica gtt Moleculaire genetica gtt Genome, Human Human molecular genetics Molecular Biology Molekulargenetik (DE-588)4039987-4 gnd Humangenetik (DE-588)4072653-8 gnd |
| subject_GND | (DE-588)4039987-4 (DE-588)4072653-8 (DE-588)4123623-3 |
| title | Human molecular genetics |
| title_alt | Human molecular genetics 3 |
| title_auth | Human molecular genetics |
| title_exact_search | Human molecular genetics |
| title_full | Human molecular genetics Tom Strachan and Andrew P. Read |
| title_fullStr | Human molecular genetics Tom Strachan and Andrew P. Read |
| title_full_unstemmed | Human molecular genetics Tom Strachan and Andrew P. Read |
| title_short | Human molecular genetics |
| title_sort | human molecular genetics |
| topic | Génétique moléculaire humaine Medische genetica gtt Moleculaire genetica gtt Genome, Human Human molecular genetics Molecular Biology Molekulargenetik (DE-588)4039987-4 gnd Humangenetik (DE-588)4072653-8 gnd |
| topic_facet | Génétique moléculaire humaine Medische genetica Moleculaire genetica Genome, Human Human molecular genetics Molecular Biology Molekulargenetik Humangenetik Lehrbuch |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=010510594&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT strachantom humanmoleculargenetics AT readandrewp humanmoleculargenetics AT strachantom humanmoleculargenetics3 AT readandrewp humanmoleculargenetics3 |