An introduction to human molecular genetics: mechanisms of inherited diseases

659 Pages·2005·14.12 MB·English

by  Jack J. Pasternak

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AN INTRODUCTION TO
Human
Molecular
Genetics
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AN INTRODUCTION TO
Human
Molecular
Genetics
Mechanisms of
Inherited Diseases
Second Edition
Jack J. Pasternak
University of Waterloo
Ontario,Canada
A JOHN WILEY & SONS,INC.,PUBLICATION
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Copyright © 2005 by John Wiley & Sons,Inc.All rights reserved.
Published by John Wiley & Sons,Inc.,Hoboken,New Jersey.
Published simultaneously in Canada.
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ISBN:0-471-47426-6
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For my family
Lili (I-1) I 1
Lisa (II-2)
Dahna (II-3)
Martin (II-1)
II
Mike (II-4)
1 2 3 4
Madelaine (III-1)
Miranda (III-2)
Nina (III-3)
Maya (III-4) III
1 2 3 4
Ifwe begin with certainties,we shall end in doubts;but ifwe begin with
doubts,and are patient in them,we shall end in certainties.
FRANCIS BACON (1561–1626)
Our doubts are traitors,
And make us lose the good we oft might win,
By fearing to attempt.
WILLIAM SHAKESPEARE (1564–1616)
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Contents
Preface xvii
Preface to the First Edition xix
chapter 1
Understanding Human Disease 1
Human Genetic Disease 2
Human Genetics from 1900 to 1957 5
Eugenics: Genetics Misinterpreted 9
The Molecularization of Genetics 11
Genes and Phenotypes 12
from the human genetics files
OMIM:An Important Online Source of Information About Human
Genetic Disorders 14
Key Terms 17
Summary 17
References 18
Review Questions 18
chapter 2
The Genetic System: Chromosomes 19
Human Chromosomes 19
Maintaining the Chromosome Number 19
Cell Division Cycle: The Mitotic Process 20
The Meiotic Process 22
Characterizing Human Chromosomes 24
Chromosome Abnormalities 28
Whole Chromosome Changes: Aneuploidy 28
Chromosome Structural Changes 30
from the human genetics files
Determining the Phases of the Cell Cycle 32
Key Terms 35
Summary 35
References 36
Review Questions 36
vii
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viii Contents
chapter 3
The Genetic System: Mendel’s Laws of Inheritance
and Genetic Linkage 37
Dominance, Recessiveness, and Segregation 38
Independent Assortment 41
Genetic Linkage 44
Constructing Genetic Maps 47
Three-Point Cross 48
Chi-Square Distribution: Testing for Significance 52
Multiple Alleles 54
Human Genetics 55
Autosomal Dominant Inheritance 58
Autosomal Recessive Inheritance 59
X-Linked Inheritance 60
Using Pedigrees to Study Human Genetic Disorders 61
from the human genetics files
Calculating Mendelian Frequencies 65
Detection and Estimation of Genetic Linkage in Humans 66
The Logarithm of the Likelihood Ratio Method of Linkage Analysis:
LOD Score 67
Key Terms 71
Summary 72
References 72
Review Questions 73
chapter 4
The Molecular Biology of the Gene 75
Properties of Genetic Material 75
Structure of DNA 76
DNA Replication 79
Decoding Genetic Information: RNA and Protein 79
Translation 85
Regulation of mRNA Transcription 89
from the human genetics files
Hemoglobinopathies and Thalassemias:An Abundance of Mutations 92
Nucleotide Sequence Alteration: Mutation 94
Mutations of Structural Genes 95
Nomenclature for Mutations 100
Dominant Mutations and Genetic Disorders 102
Key Terms 104
Summary 104
References 105
Review Questions 106
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Contents ix
chapter 5
Recombinant DNA Technology 107
Restriction Endonucleases 108
Cloning Vectors 115
Plasmid Cloning Vector pUC19 116
Screening DNA Constructs by DNA Hybridization 119
In Situ Hybridization 122
Chemical Synthesis of DNA 122
Sequencing DNA 124
Polymerase Chain Reaction 130
Human-Rodent Somatic Cell Hybrids 131
Human DNA Libraries 137
Genomic Libraries 137
Chromosome DNA Libraries 139
from the human genetics files
Multicolor Karyotyping:Coloring Chromosomes 143
Region-Specific Chromosome Libraries 144
Constructing a cDNA Library 145
Key Terms 149
Summary 149
References 151
Review Questions 151
chapter 6
Genetic and Physical Mapping of the Human
Genome 153
Genetic Mapping of Human Chromosomes 153
Genetic Polymorphism 153
Restriction Fragment Length Polymorphism 155
Short Tandem Repeat Polymorphism 158
Mapping of a Genetic Disease Locus to a Chromosome Location 159
Multilocus Mapping of Human Chromosomes 163
Inserting a Disease Gene into a Linkage Map 165
Homozygosity Mapping 168
Linkage Disequilibrium Mapping 169
Radiation Hybrid Mapping 171
Genotyping Single-Nucleotide Polymorphisms 174
Physical Mapping of the Human Genome 181
Assembling Contigs from BAC Libraries 181
from the human genetics files
Comparative Genetic Maps 182
Integration of Cytogenetic, Genetic, and Physical Maps 184
Key Terms 186
Summary 186
References 186
Review Questions 187