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An introduction to human molecular genetics: mechanisms of inherited diseases PDF

659 Pages·2005·14.12 MB·English
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PR.qxd 3/5/05 3:26 PM Page i AN INTRODUCTION TO Human Molecular Genetics PR.qxd 3/5/05 3:26 PM Page ii PR.qxd 3/5/05 3:26 PM Page iii 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 iv Copyright © 2005 by John Wiley & Sons,Inc.All rights reserved. Published by John Wiley & Sons,Inc.,Hoboken,New Jersey. Published simultaneously in Canada. No part of this publication may be reproduced,stored in a retrieval system,or transmitted in any form or by any means,electronic,mechanical,photocopying,recording,scanning,or otherwise, except as permitted under section 107 or 108 of the 1976 United States Copyright Act,without either the prior written permission of the Publisher,or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center,Inc.,222 Rosewood Drive,Danvers, MA 01923,978-750-8400,fax 978-646-8600,or on the web at www.copyright.com.Requests to the Publisher for permission should be addressed to the Permissions Department,John Wiley & Sons, Inc.,111 River Street,Hoboken,NJ 07030,(201) 748-6011,fax (201) 748-6008. Limit of Liability/Disclaimer of Warranty:While the publisher and author have used their best efforts in preparing this book,they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose.No warranty may be created or extended by sales representatives or written sales materials.The advice and strategies contained herein may not be suitable for your situation.You should consult with a professional where appropriate.Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages,including but not limited to special,incidental,consequential,or other damages. For general information on our other products and services please contact our Customer Care Department within the U.S.at 877-762-2974,outside the U.S.at 317-572-3993 or fax 317-572-4002. 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 ofCongress 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 v 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) PR.qxd 3/5/05 3:26 PM Page vi PR.qxd 3/5/05 3:26 PM Page vii 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 viii 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 PR.qxd 3/5/05 3:26 PM Page ix 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

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