An Introduction to Human Molecular Genetics - Mechanisms of Inherited Diseases 2nd ed - J. Pasternak (Wiley, 2005) WW PDF
Preview An Introduction to Human Molecular Genetics - Mechanisms of Inherited Diseases 2nd ed - J. Pasternak (Wiley, 2005) WW
AN INTRODUCTION TO Human Molecular Genetics PR.qxd 3/5/05 3:26 PM Page i PR.qxd 3/5/05 3:26 PM Page ii 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 PR.qxd 3/5/05 3:26 PM Page iii 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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Wiley also publishes its books in a variety of electronic formats. Some content that appears in print, however, may not be available in electronic format. Library of Congress Cataloging-in-Publication Data is available. ISBN: 0-471-47426-6 Printed in the United States of America 10 9 8 7 6 5 4 3 2 1 PR.qxd 3/5/05 3:26 PM Page iv For my family Lili (I-1) Lisa (II-2) Dahna (II-3) Martin (II-1) Mike (II-4) Madelaine (III-1) Miranda (III-2) Nina (III-3) Maya (III-4) If we begin with certainties, we shall end in doubts; but if we 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) II I 2 1 1 3 4 III 2 1 3 4 PR.qxd 3/5/05 3:26 PM Page v PR.qxd 3/5/05 3:26 PM Page vi 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 PR.qxd 3/5/05 3:26 PM Page vii 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 viii Contents PR.qxd 3/5/05 3:26 PM Page viii 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 Contents ix PR.qxd 3/5/05 3:26 PM Page ix
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