Concepts of genetics 11th global edition palladino 1

www.downloadslide.com Concepts of Genetics For these Global Editions, the editorial team at Pearson has collaborated with educators across the world to address a wide range of subjects and requirements, equipping students with the best possible learning tools This Global Edition preserves the cutting-edge approach and pedagogy of the original, but also features alterations, customization, and adaptation from the North American version Global edition Global edition Global edition Concepts of Genetics   eleventh edition William S Klug • Michael R Cummings Charlotte A Spencer • Michael A Palladino eleventh edition Klug • Cummings Spencer • Palladino This is a special edition of an established title widely used by colleges and universities throughout the world Pearson published this exclusive edition for the benefit of students outside the United States and Canada If you purchased this book within the United States or Canada, you should be aware that it has been imported without the approval of the Publisher or Author Pearson Global Edition Klug_1292077263_mech.indd 27/08/15 6:42 PM www.downloadslide.com C once p t s E L E V E N T H G L O B A L o f E D I T I O N E D I T I O N William S Klug T he C ollege O f N e w J e r s e y Michael R Cummings I llinoi s I n s tit u te o f T echnolog y Charlotte A Spencer Unive r s it y o f A lbe r ta Michael A Palladino M onmo u th Unive r s it y With contributions by Darrell Killian C olo r ado C ollege Boston Columbus Indianapolis New York San Francisco Amsterdam Cape Town Dubai London Madrid Milan Munich Paris Montréal Toronto Delhi Mexico City São Paulo Sydney Hong Kong Seoul Singapore Taipei Tokyo A01_KLUG7260_11_GE_FM.indd 27/08/15 4:02 PM www.downloadslide.com Credits and acknowledgments for materials borrowed from other sources and reproduced, with permission, in this textbook appear on the appropriate page within the text Pearson Education Limited Edinburgh Gate Harlow Essex CM20 2JE England and Associated Companies throughout the world Visit us on the World Wide Web at: www.pearsonglobaleditions.com © Pearson Education Limited 2016 The rights of William S Klug, Michael R Cummings, Charlotte A Spencer, and Michael A Palladino to be identified as the authors of this work have been asserted by them in accordance with the Copyright, Designs and Patents Act 1988 Authorized adaptation from the United States edition, entitled Concepts of Genetics, 11th edition, ISBN 978-0-321-94891-5, by William S Klug, Michael R Cummings, Charlotte A Spencer, and Michael A Palladino, published by Pearson Education © 2015 All rights reserved 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 or otherwise, without either the prior written permission of the publisher or a license permitting restricted copying in the United Kingdom issued by the Copyright Licensing Agency Ltd, Saffron House, 6–10 Kirby Street, London EC 1N 8TS All trademarks used herein are the property of their respective owners.The use of any trademark in this text does not vest in the author or publisher any trademark ownership rights in such trademarks, nor does the use of such trademarks imply any affiliation with or endorsement of this book by such owners Editor-in-Chief: Beth Wilbur Senior Acquisitions Editor: Michael Gillespie Executive Director of Development: Deborah Gale Executive Editorial Manager: Ginnie Simione-Jutson Project Editor: Dusty Friedman Editorial Assistant: Chloe Veylit Text Permissions Project Manager: Timothy Nicholls Text Permissions Specialist: PreMedia Global USA, Inc Program Manager Team Lead: Michael Early Program Manager: Anna Amato Project Manager Team Lead: David Zielonka Project Manager: Lori Newman Project Manager—Instructor Media: Edward Lee Production Management and Composition: Cenveo® Publisher Services Copyeditor: Betty Pessagno Proofreader: Joanna Dinsmore Senior 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published, or sold in whole or in part, without prior written permission from the publisher Many of the designations by manufacturers and sellers to distinguish their products are claimed as trademarks Where those designations appear in this book, and the publisher was aware of a trademark claim, the designations have been printed in initial caps or all caps MasteringGenetics is a trademark, in the U.S and/or other countries, of Pearson Education, Inc or its affiliates ISBN 10: 1-292-07726-3 ISBN 13: 978-1-292-07726-0 British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library 10 Typeset by Cenveo® Publisher Services Printed and bound by Vivar in Malaysia A01_KLUG7260_11_GE_FM.indd 27/08/15 4:02 PM www.downloadslide.com Dedication To Kathy, Lee Ann, Bob, and Cindy, who mean the very most to us, and serve as our respective foundations when we are writing, and when we are not WSK, MRC, CAS, and MAP A01_KLUG7260_11_GE_FM.indd 27/08/15 4:02 PM www.downloadslide.com About the Authors William S Klug is an Emeritus Professor of Biology at The College of New Jersey (formerly Trenton State College) in Ewing, New Jersey, where he served as Chair of the Biology Department for 17 years He received his B.A degree in Biology from Wabash College in Crawfordsville, Indiana, and his Ph.D from Northwestern University in Evanston, Illinois Prior to coming to The College of New Jersey, he was on the faculty of Wabash College as an Assistant Professor, where he first taught genetics, as well as general biology and electron microscopy His research interests have involved ultrastructural and molecular genetic studies of development, utilizing oogenesis in Drosophila as a model system He has taught the genetics course as well as the senior capstone seminar course in Human and Molecular Genetics to undergraduate biology majors for over four decades He was the recipient in 2001 of the first annual teaching award given at The College of New Jersey, granted to the faculty member who “most challenges students to achieve high standards.” He also received the 2004 Outstanding Professor Award from Sigma Pi International, and in the same year, he was nominated as the Educator of the Year, an award given by the Research and Development Council of New Jersey Michael R Cummings is Research Professor in the Department of Biological, Chemical, and Physical Sciences at Illinois Institute of Technology, Chicago, Illinois For more than 25 years, he was a faculty member in the Department of Biological Sciences and in the Department of Molecular Genetics at the University of Illinois at Chicago He has also served on the faculties of Northwestern University and Florida State University He received his B.A from St Mary’s College in Winona, Minnesota, and his M.S and Ph.D from Northwestern University in Evanston, Illinois In addition to this text and its companion volumes, he has also written textbooks in human genetics and general biology for nonmajors His research interests center on the molecular organization and physical mapping of the heterochromatic regions of human acrocentric chromosomes At the undergraduate level, he teaches courses in Mendelian and molecular genetics, human genetics, and general biology, and has received numerous awards for teaching excellence given by university faculty, student organizations, and graduating seniors Charlotte A Spencer is a retired Associate Professor from the Department of Oncology at the University of Alberta in Edmonton, Alberta, Canada She has also served as a faculty member in the Department of Biochemistry at the University of Alberta She received her B.Sc in Microbiology from the University of British Columbia and her Ph.D in Genetics from the University of Alberta, followed by postdoctoral training at the Fred Hutchinson Cancer Research Center in Seattle, Washington Her research interests involve the regulation of RNA polymerase II transcription in cancer cells, cells infected with DNA viruses, and cells traversing the mitotic phase of the cell cycle She has taught courses in biochemistry, genetics, molecular biology, and oncology, at both undergraduate and graduate levels In addition, she has written booklets in the Prentice Hall Exploring Biology series, which are aimed at the undergraduate nonmajor level Michael A Palladino is Dean of the School of Science and Professor of Biology at Monmouth University in West Long Branch, New Jersey He received his B.S degree in Biology from Trenton State College (now known as The College of New Jersey) and his Ph.D in Anatomy and Cell Biology from the University of Virginia He directs an active laboratory of undergraduate student researchers studying molecular mechanisms involved in innate immunity of mammalian male reproductive organs and genes involved in oxygen homeostasis and ischemic injury of the testis He has taught a wide range of courses for both majors and nonmajors and currently teaches genetics, biotechnology, endocrinology, and laboratory in cell and molecular biology He has received several awards for research and teaching, including the 2009 Young Investigator Award of the American Society of Andrology, the 2005 Distinguished Teacher Award from Monmouth University, and the 2005 Caring Heart Award from the New Jersey Association for Biomedical Research He is co-author of the undergraduate textbook Introduction to Biotechnology, Series Editor for the Benjamin Cummings Special Topics in Biology booklet series, and author of the first booklet in the series, Understanding the Human Genome Project A01_KLUG7260_11_GE_FM.indd 27/08/15 4:02 PM www.downloadslide.com Brief Contents Par t O ne G enes, Ch rom Osome s , and He redit y Par t Fo ur Genomic s 20 Recombinant DNA Technology  523 Introduction to Genetics  35 21 Genomics, Bioinformatics, and Proteomics  556 Mitosis and Meiosis  50 22 Mendelian Genetics  74 Applications and Ethics of Genetic Engineering and Biotechnology  603 Extensions of Mendelian Genetics  104 Chromosome Mapping in Eukaryotes  138 Genetic Analysis and Mapping in Bacteria and Bacteriophages  168 Sex Determination and Sex Chromosomes  198 Chromosome Mutations: Variation in Number and Arrangement  222 Extranuclear Inheritance  248 Par t Tw o DNA : Stru ctu re , Re plication, and Va riation 10 DNA Structure and Analysis  265 11 DNA Replication and Recombination  295 12 DNA Organization in Chromosomes  322 Par t Th ree G ene E xp re ssion , Reg ulation , and D evelop ment Par t Five Genetics o f O rganis ms and Population s 23 Quantitative Genetics and Multifactorial Traits  638 24 Neurogenetics  659 25 Population and Evolutionary Genetics  681 S pecial To pic s in M ode r n Genetics Epigenetics  708 Emerging Roles of RNA  718 DNA Forensics  735 Genomics and Personalized Medicine  746 Genetically Modified Foods  758 Gene Therapy  772 Appendix A   Selected Readings  787 13 The Genetic Code and Transcription  342 Appendix B   Answers to Selected Problems  799 14 Translation and Proteins  371 Glossary  841 15 Gene Mutation, DNA Repair, and Transposition  401 Credits  863 16 Regulation of Gene Expression in Prokaryotes  430 17 Regulation of Gene Expression in Eukaryotes  451 18 Developmental Genetics  479 19 Cancer and Regulation of the Cell Cycle  503 Index  867 A01_KLUG7260_11_GE_FM.indd 27/08/15 4:02 PM www.downloadslide.com Explore Cutting Edge Topics EXPANDED! Six Special Topics NEW! End-of-Chapter Questions are provided for each Special Topic chapter to help students review key ideas and to facilitate class discussions Questions are assignable through MasteringGenetics New! Photos and illustrations have been added throughout the text A01_KLUG7260_11_GE_FM.indd methods How does this method compare with Agrobacterium tumefaciens-mediated transformation? How positive and negative selection techniques contribute to the development of GM crops? 10 Describe how the Roundup-Ready soybean variety was developed, and what genes were used to transform the soybean plants M30_KLUG8915_11_ST05_pp724-737.indd 724 20/05/14 5:58 PM discussion Questions What are the laws regulating the development, approval, and use of GM foods in your region and nationally? Do you think that foods containing GM(a) ingredients should be labeled as such? What would be the advantages and disadvantages to such a strategy? One of the major objections to GM foods is that they may be harmful to human health Do you agree or disagree, and why? (b) Rods AAV7 AAV8 RPE AAV2 AAV7 AAV8 AAV9 rh8R rh64R1 Cones AAV9 V2 AA V8 AA AAV7 SPECIAL TOPIC ■■ developed, only a few are widely used What are these varieties, 724 and how prevalent are they? How does glyphosate work, and how has it been used with GM crops to increase agricultural yields? Describe the mechanisms by which the Cry proteins from Bacillus thuringiensis act as insecticides V9 AA rh8R R1 ■■ T hroughout the ages, humans have used selective violence On August 8, 2013, 400 protesters broke through breeding techniques to create plants and animals security fences surrounding a field trial of Golden Rice in with desirable genetic traits By selecting organisms the Bicol region of the Philippines (ST Figure 5–1) Within with naturally occurring or mutagen-induced variations 15 minutes, they had uprooted and trampled most of the and breeding them to establish the phenotype, we have GM rice plants The attackers argued that Golden Rice was evolved varieties that now feed our growing populations a threat to human health and biodiversity and would lead to and support our complex civilizations Western corporate control of local food crops Although we have had tremendous success shuffling Opposition to GM foods is not unique to Golden Rice genes through selective breeding, the In 2013, approximately two million people process is a slow one When recombinant marched against GM foods in rallies held DNA technologies emerged in the 1970s “genetic engineering in 52 countries Some countries have outand 1980s, scientists realized that they of animals and right bans on all GM foods, whereas others could modify agriculturally significant embrace the technologies Opponents cite plants promised organisms in a more precise and rapid safety and environmental concerns, while an exciting new way—by identifying and cloning genes some scientists and commercial interests phase in scientific that confer desirable traits, then introducextol the almost limitless virtues of GM ing these genes into organisms Genetic agriculture, foods The topic of GM food attracts hyperengineering of animals and plants prombole and exaggerated rhetoric, informawith increased ised an exciting new phase in scientific tion, and misinformation—on both sides of productivity, reduced agriculture, with increased productivity, the debate pesticide use, and reduced pesticide use, and enhanced So, what are the truths about GM enhanced flavor and foods? In this Special Topic chapter, we flavor and nutrition Beginning in the 1990s, scientists crewill introduce the science behind GM foods nutrition.” ated a large number of genetically modiand examine the promises and problems fied (GM) food varieties The first one, approved for sale in 1994, was the Flavr Savr tomato—a tomato that stayed firm and ripe longer than non-GM tomatoes Soon afterward, other GM foods were developed: papaya and zucchini with resistance to virus infection, canola containing the tropical oil laurate, corn and cotton plants with resistance to insects, and soybeans and sugar beets with tolerance to agricultural herbicides By 2012, more than 200 different GM crop varieties had been created Worldwide, GM crops are planted on 170 million hectares of arable land, with a global value of $15 billion for GM seeds Although many people see great potential for GM dISCUSSIO n QUE S TIOn S 771 foods—to help address malnutrition in a world with a growing human population and climate change—others question the technology, oppose GM food development, and somereview Questions times resort to violence to stop the introduction of GM variS T F igur e 5–1 Anti-GM protesters attacking Golden Rice eties.compare Even with Golden of ricehave thatbeen contains How genetically modified organisms organ-Rice—a variety What measures taken tothe alleviate field vitamin defiOnA August 8, 2013, protesters in the Philippines broke isms created through selective breeding? in developing To date, howthrough successfulahave vitamin A precursor and wasciencies developed on a countries? humanitarian security fence and destroyed an experimental field of thesevitamin strategiesA been? Can current GM crops be considerednonprofit as transgenic or cisgenic? Golden Rice plants basis to help alleviate deficiencies in the Why? What is Golden Rice 2, and how was it created? been the target of opposition and (Photo Of the approximately 200 GM cropdeveloping varieties that world—has have been Describe how plants can be transformed using courtesy biolisticPhilippine Department of Agriculture Regional Field Unit 5) rh 64 Epigenetics New! Emerging Roles of RNA ■■ DNA Forensics ■■ Genomics and Personalized Medicine ■■ New! Genetically Modified Foods ■■ New! Gene Therapy ■■ Genetically Modified Foods SPECIAL TOPIC in Modern Genetics mini-chapters concisely explore cutting-edge, engaging, relevant topics, and three are new to the Eleventh Edition: S pe ci a l Topi c S i n M od er n GeneT i cS 27/08/15 4:02 PM www.downloadslide.com Explore Classic and Modern Approaches NEW! Chapter 21 Chapter 10 Evolving Concept of the Gene sections, integrated in key chapters, highlight how scientists’ understanding of the gene has changed over time Chapters 3, 4, 5, 6, 10, 12, 14, 16, 21 NEW! Modern Approaches to Understanding Gene Function feature introduces the impact of modern gene targeting approaches on our understanding of gene function Each entry explores experimental approaches, analyzes data, and relates to a concept discussed in the chapter Includes discussion questions Topics include: ■■ Identifying Mendel’s Gene for Regulating White Flower Color in Peas (Ch 3) ■■ Drosophila Sxl Gene Induces Female Development (Ch 7) ■■ Mouse Models of Down Syndrome (Ch 8) ■■ Lethal Knockouts of DNA Ligase Genes (Ch 11) ■■ Transposon-Mediated Mutations Reveal Genes Involved in Colorectal Cancer (Ch 15) A01_KLUG7260_11_GE_FM.indd ■■ MicroRNAs Regulate Ovulation in Female Mice (Ch 17) ■■ Single-Gene Signaling Mechanism Reveals Secrets to Head Regeneration in Planaria (Ch 18) ■■ RbAp48 and a Potential Molecular Mechanism for Age-Related Memory Loss (Ch.24) 27/08/15 4:02 PM molecular hybridization studies They tried hybridizing this RNA to the DNA of both phages and bacteria in separate experiments The RNA hybridized only with the phage DNA, showing that it was complementary in base sequence to the viral genetic information The results of these experiments agree with the concept of a messenger RNA (mRNA) being made on a DNA template and then directing the synthesis of specific proteins in association with ribosomes This concept was formally proposed by Franỗois Jacob and Jacques Monod in 1961 as part of a model for gene regulation in bacteria Since then, mRNA has been isolated and thoroughly studied There is no longer any question about its role in genetic processes enzyme, contains the subunits a2bb′s and has a molecular weight of almost 500,000 Da While there is some variation in the subunit composition of other bacteria, it is the b and b′ polypeptides that provide the catalytic mechanism and active site for transcription As we will see, the s (sigma) factor [Figure 13–9(a)] plays a regulatory function in the initiation of RNA transcription While there is but a single form of the enzyme in E coli, there are several different s factors, creating variations of the polymerase holoenzyme On the other hand, eukaryotes display three distinct forms of RNA polymerase, each consisting of a greater number of polypeptide subunits than in bacteria In this section, we will discuss the process of transcription in prokaryotes We will return to a discussion of eukaryotic transcription later in this chapter www.downloadslide.com Learn and Practice Problem Solving 64 13.10 rna polymerase directs rna Synthesis To prove that RNA can be synthesized on a DNA template, it was necessary to demonstrate that there is an enzyme capable of directing this synthesis By 1959, several investigators, including Samuel Weiss, had independently discovered such a molecule in rat liver Called RNA polymerase, it has the same general substrate requirements as does DNA polymerase, the major exception being that the substrate nucleotides contain the ribose rather than the deoxyribose form of the sugar Unlike DNA polymerase, no primer is required to initiate synthesis The overall reaction summarizing the synthesis of RNA on a DNA template can be expressed as Learn problem- solving skills by pausing to complete integrated Now Solve This problems DNA n(NTP) enzyme ¡ (NMP)n + n(PPi) As the equation reveals, nucleoside triphosphates (NTPs) serve as substrates for the enzyme, which catalyzes the polymerization of nucleoside monophosphates (NMPs), or nucleotides, into a polynucleotide chain (NMP)n Nucleotides are linked during synthesis by 5′ to 3′ 13–3 The following represent deoxyribonucleotide sequences in the template strand of DNA: Sequence 1: 5′-C T T T T T TGCCAT-3′ Sequence 2: 5′-ACATCAATAAC T-3′ Sequence 3: 5′-TACAAGGGT TC T-3′ As a student, you will be asked to demonstrate your knowledge of transmission genetics by solving various problems Success at this task requires not only comprehension of theory but also its application to more practical genetic situations Most students find problem solving in genetics to be both challenging and rewarding This section is designed to provide basic insights into the reasoning essential to this process Genetics problems are in many ways similar to word problems in algebra The approach to solving them is identical: (1) analyze the problem carefully; (2) translate words into symbols and define each symbol precisely; and (3) choose and apply a specific technique to solve the problem The first two steps are the most critical The third step is largely mechanical The simplest problems state all necessary information about a P1 generation and ask you to find the expected ratios of the F1 and F2 genotypes and/or phenotypes Always follow these steps when you encounter this type of problem: (a) For each strand, determine the mRNA sequence that would be derived from transcription (b) Using Figure 13–7, determine the amino acid sequence that is encoded by these mRNAs (c) For Sequence 1, what is the sequence of the partner DNA strand? (a) Determine insofar as possible the genotypes of the individuals in the P1 generation (d) Repeat the process to obtain information about the F2 generation Determining the genotypes from the given information requires that you understand the basic theory of transmission genetics Consider this problem: A recessive mutant allele, black, causes a very dark body in Drosophila when homozygous The normal wild-type color is described as gray What F1 phenotypic ratio is predicted when a black female is crossed to a gray male whose father was black? To work out this problem, you must understand dominance and recessiveness, as well as the principle of segregation Furthermore, you must use the information about the male parent’s father Here is one logical approach to solving this problem: The female parent is black, so she must be homozygous for the mutant allele (bb) The male parent is gray and must therefore have at least one dominant allele (B) His father was black (bb), and he received one of the chromosomes bearing these alleles, so the male parent must be heterozygous (Bb) From this point, solving the problem is simple: H i NT: This problem asks you to consider the outcome of the transfer of complementary information from DNA to RNA and to determine the amino acids encoded by this information The key to its solution is to remember that in RNA, uracil is complementary to adenine, and that while DNA stores genetic information in the cell, the code that is translated is contained in the RNA complementary to the template strand of DNA making up a gene Solution: First, assign gene symbols to each pair of contrasting traits Use the lowercase first letter of each recessive trait to designate that trait, and use the same letter in uppercase to designate the dominant trait Thus, C and c indicate full and constricted pods, respectively, and W and w indicate the round and wrinkled phenotypes, respectively Determine the genotypes of the P1 generation, form the gametes, combine them in the F1 generation, and read off the phenotype(s):     CcWw   full, round   You can immediately see that the F1 generation expresses both dominant phenotypes and is heterozygous for both gene pairs Thus, you expect that the F2 generation will yield the classic Mendelian ratio of 9:3:3:1 Let’s work it out anyway, just to confirm this expectation, using the forked-line method Both gene pairs are heterozygous and can be expected to assort independently, so we can predict the F2 outcomes from each gene pair separately and then proceed with the forked-line method The F2 offspring should exhibit the individual traits in the following proportions: Cc Cc T CC Cc full cC cc constricted Ww Ww T WW round Ww wW ww wrinkled Strengthen your problem- * Bb solving strategies by studying the step-by-step solutions and rationales modeled in Insights and Solutions Heterozygous gray male B b 24/03/14 3:49 PM CCww full, wrinkled T Cw ˛˝¸ bb Homozygous black female ccWW constricted, round T cW Gametes:   F: P1: ˛˝¸ strategies by studying hints, and checking your work against the Answers Appendix Apply the approach we just studied to the following problems Mendel found that full pea pods are dominant over constricted pods, while round seeds are dominant over wrinkled seeds One of his crosses was between full, round plants and constricted, wrinkled plants From this cross, he obtained an F1 generation that was all full and round In the F2 generation, Mendel obtained his classic 9:3:3:1 ratio Using this information, determine the expected F1 and F2 results of a cross between homozygous constricted, round and full, wrinkled plants (b) Determine what gametes may be formed by the P1 parents (c) Recombine the gametes by the Punnett square or the forked-line method, or if the situation is very simple, by inspection From the genotypes of the F1 generation, determine the phenotypes Read the F1 phenotypes Apply problem-solving G8915_11_C13_pp308-336.indd 321 M endel ian Genet ic s insiGhts and solutions b Bb bb F1 1/2 Heterozygous gray males and females, Bb 1/2 Homozygous black males and females, bb M03_KLUG8915_11_C03_pp040-069.indd 64 Using these proportions to complete a forked-line diagram confirms the 9:3:3:1 phenotypic ratio (Remember that this ratio represents proportions of 9/16:3/16:3/16:1/16.) Note that we are applying the product law as we compute the final probabilities: 15/01/14 4:36 PM MasteringGenetics™ MasteringGenetics helps students master key genetics concepts while reinforcing problem solving skills with hints and feedback specific to their misconceptions Tutorial topics include: Pedigree analysis Sex linkage ■■ Gene interactions A01_KLUG7260_11_GE_FM.indd DNA replication RNA processing ■■ Genomics ■■ ■■ ■■ ■■ 27/08/15 4:02 PM 162 Geneti c analyS i S and M appi n G in B ac t e r ia a n d B ac t e r iop h aG eS 19 In an analysis of rII mutants, complementation testing yielded the following results: www.downloadslide.com Mutants Results (1/2 lysis) 1, 1, 1, 1, 1 2 21 Using mutants and from the previous problem, following mixed infection on E coli B, progeny viruses were plated in a series of dilutions on both E coli B and K12 with the following results (a) What is the recombination frequency between the two mutants? Strain Plated Predict the results of testing and 3, and 4, and and together 20 If further testing of the mutations in Problem 19 yielded the following results, what would you conclude about mutant 5? Mutants Results 2, 3, 4, 2 Dilution Plaques E coli B 10-5 E coli K12 10-1 (b) Another mutation, 6, was tested in relation to mutations through from the previous problems In initial testing, mutant complemented mutants and In recombination testing with 1, 4, and 5, mutant yielded recombinants with and 5, but not with What can you conclude about mutation 6? extra-Spicy problems “How Do We Know?” questions Visit for instructor-assigned tutorials and problems 22 During the analysis of seven rII mutations in phage T4, mutants 1, 2, and were in cistron A, while mutants 3, 4, and were in cistron B Of these, mutant was a deletion overlapping mutant The remainder were point mutations Nothing was known about mutant Predict the results of complementation (1 or –) between and 2; and 3; and 4; and and 23 In studies of recombination between mutants and from the previous problem, the results shown in the following table were obtained ask students to identify and examine the experimental basis underlying important concepts Strain Concept NEW! Questions ask students to check their understanding of Key Concepts Dilution Plaques E coli B 10-7 Phenotypes r E coli K12 10-2 (a) Calculate the recombination frequency (b) When mutant was tested for recombination with mutant 1, the data were the same as those shown above for strain B, but not for K12 The researcher lost the K12 data, but remembered that recombination was ten times more frequent than when mutants and were tested What were the lost values (dilution and colony numbers)? (c) Mutant (Problem 22) failed to complement any of the other mutants (1–6) Define the nature of mutant 24 In Bacillus subtilis, linkage analysis of two mutant genes affecting the synthesis of two amino acids, tryptophan (trp2- ) and tyrosine (tyr1- ), was performed using transformation Examine the following data and draw all possible conclusions regarding linkage What is the purpose of Part B of the experiment? [Reference: E Nester, M Schafer, and J Lederberg (1963).] 25 An Hfr strain is used to map three genes in an interrupted mating experiment The cross is Hfr > a + b + c + rif * F -> a - b - c rif r (No map order is implied in the listing of the alleles; rif r is resistance to the antibiotic rifampicin.) The a + gene is required for the biosynthesis of nutrient A, the b + gene for nutrient B, and c + for nutrient C The minus alleles are auxotrophs for these nutrients The cross is initiated at time = 0, and at various times, the mating mixture is plated on three types of medium Each plate contains minimal medium (MM) plus rifampicin plus specific supplements that are indicated in the following table (The results for each time interval are shown as the number of colonies growing on each plate.)     Time of Interruption 10 15 0 21 Nutrients B and C 23 40 Nutrients A and C 25 60 82 (a) What is the purpose of rifampicin in the experiment? (b) Based on these data, determine the approximate location on the chromosome of the a, b, and c genes relative to one another and to the F factor (c) Can the location of the rif gene be determined in this experiment? If not, design an experiment to determine the location of rif relative to the F factor and to gene b 26 A plaque assay is performed beginning with mL of a solution containing bacteriophages This solution is serially diluted three times by combining 0.1 mL of each sequential dilution with 9.9 mL of liquid medium Then 0.1 mL of the final dilution is plated in the plaque assay and yields 17 plaques What is the initial density of bacteriophages in the original mL? 27 In a cotransformation experiment, using various combinations of genes two at a time, the following data were produced Determine which genes are “linked” to which others Extra-Spicy Problems challenge students to solve     problems, 196 trp tyr complex many based trp tyr 328 A trp tyr trp tyr     367 trp tyr on data derived from primary   190 trp tyr trp tyr trp tyr 256 trp tyr B and genetics literature   trp tyr trp tyr Donor DNA + + + 2 + Recipient Cell 2 1 Transformants + - - + + + + - - + + + No M06_KLUG8915_11_C06_pp134-163.indd 162 18/0 MasteringGenetics™ Prepare students for the challenging problems they will see on tests and exams: question types include sorting, labeling, entering numerical information, multiple choice, and fill-in-theblank NEW! 140 Additional Practice Problems offer more opportunities to develop problem solving skills These questions appear only in MasteringGenetics, and they include targeted wrong answer feedback to help students learn from their mistakes Complete the Problems and Discussion Questions at the end of each chapter 90% of questions are now available in MasteringGenetics A01_KLUG7260_11_GE_FM.indd 20 Nutrients A and B 27/08/15 4:02 PM www.downloadslide.com Succeed with MasteringGenetics MasteringGenetics is a powerful online learning and assessment system proven to help students learn problem-solving skills You’ll find activities for use before class, during class, and after class Before Class After Class You can assign a broad range of homework including tutorials, activities, practice problems, end of chapter questions, and test bank questions Homework, Homework Quizzing, Quizzing, and and Testing Testing Pre-built reading quizzes for every Pre-lecture Pre-lecture Assignments Assignments chapter hold students accountable for reading the chapter and familiarizing themselves with basic concepts before coming to class Mastering Continuously Adaptive Learning Catalytics, Mastering Media During Class NEW! Learning Catalytics is a “bring your own device” (smartphone, tablet, or laptop) assessment and active classroom system that expands the possibilities for student engagement Using Learning Catalytics, genetics instructors can deliver a wide range of autogradable or open-ended questions that test content knowledge and build critical thinking skills Instructors can create their own questions, draw from community content shared by colleagues, or access Pearson’s new library of question clusters that explore challenging topics through a series of 2-5 questions that focus on a single scenario or data set, build in difficulty, and require higher-level thinking A01_KLUG7260_11_GE_FM.indd 10 27/08/15 4:02 PM www.downloadslide.com Contents Preface  28 Par t One Gene s, Ch romo somes , and Her edit y Introduction to Genetics 35 1.1 Genetics Has a Rich and Interesting History  36 1600–1850: The Dawn of Modern Biology    36 Charles Darwin and Evolution    37 1.2 Genetics Progressed from Mendel to DNA in Less Than a Century  37 Mendel’s Work on Transmission of Traits    37 The Chromosome Theory of Inheritance: Uniting Mendel and Meiosis    38 Genetic Variation    38 The Search for the Chemical Nature of Genes: DNA or Protein?    39 1.3 Discovery of the Double Helix Launched the G E N E T I C S , T E C H N O L O G Y, A N D S O C I E T Y The Scientific and Ethical Implications of Modern Genetics    47 EXPLORING GENOMICS Internet Resources for Learning about Genomics, Bioinformatics, and Proteomics    47 Summary Points    48 Case Study Extending essential ideas of genetics beyond the classroom   49 Problems and Discussion Questions   49 Mitosis and Meiosis  50 2.1 Cell Structure Is Closely Tied to Genetic Function  51 2.2 Chromosomes Exist in Homologous Pairs in Diploid Organisms  53 2.3 Mitosis Partitions Chromosomes into Era of Molecular Genetics  39 Dividing Cells  55 The Structure of DNA and RNA    40 Gene Expression: From DNA to Phenotype    40 Proteins and Biological Function    41 Linking Genotype to Phenotype: Sickle-Cell Anemia    41 Interphase and the Cell Cycle    55 Prophase    56 Prometaphase and Metaphase    58 Anaphase    58 Telophase    59 Cell-Cycle Regulation and Checkpoints    59 1.4 Development of Recombinant DNA Technology Began the Era of DNA Cloning  42 1.5 The Impact of Biotechnology Is Continually Expanding  42 Plants, Animals, and the Food Supply    42 Biotechnology in Genetics and Medicine    43 1.6 Genomics, Proteomics, and Bioinformatics Are New and Expanding Fields  43 Modern Approaches to Understanding Gene Function    44 1.7 Genetic Studies Rely on the Use of Model Organisms  44 The Modern Set of Genetic Model Organisms    45 Model Organisms and Human Diseases    45 1.8 We Live in the Age of Genetics  46 The Nobel Prize and Genetics    46 Genetics and Society    46 11 A01_KLUG7260_11_GE_FM.indd 11 27/08/15 4:02 PM www.downloadslide.com 12 CON TEN T S 2.4 Meiosis Reduces the Chromosome Number from Diploid to Haploid in Germ Cells and Spores  60 An Overview of Meiosis    60 The First Meiotic Division: Prophase I    62 Metaphase, Anaphase, and Telophase I    63 The Second Meiotic Division    63 2.5 The Development of Gametes Varies in Spermatogenesis Compared to Oogenesis  65 2.6 Meiosis Is Critical to Sexual Reproduction in All Diploid Organisms  67 2.7 Electron Microscopy Has Revealed the Physical Structure of Mitotic and Meiotic Chromosomes  67 EXPLORING GENOMICS PubMed: Exploring and Retrieving Biomedical Literature  69 CASE STUDY  Timing is everything   69 Summary Points   69 Insights and Solutions   70 Problems and Discussion Questions   71 Mendelian Genetics 74 3.1 Mendel Used a Model Experimental Approach to Study Patterns of Inheritance  75 3.2 The Monohybrid Cross Reveals How One 3.5 Mendel’s Work Was Rediscovered in the Early Twentieth Century  85 The Chromosomal Theory of Inheritance    86 Unit Factors, Genes, and Homologous Chromosomes    86 Evolving Concept of a Gene    88 3.6 Independent Assortment Leads to Extensive Genetic Variation  88 3.7 Laws of Probability Help to Explain Genetic Events  88 The Binomial Theorem    89 3.8 Chi-Square Analysis Evaluates the Influence of Chance on Genetic Data  90 Chi-Square Calculations and the Null Hypothesis    90 Interpreting Probability Values    91 3.9 Pedigrees Reveal Patterns of Inheritance of Human Traits  93 Pedigree Conventions    93 Pedigree Analysis    94 3.10 Mutant Phenotypes Have Been Examined at the Molecular Level  95 How Mendel’s Peas Become Wrinkled: A Molecular Explanation    95 Tay—Sachs Disease: The Molecular Basis of a Recessive Disorder in Humans    96 EXPLORING GENOMICS Online Mendelian Inheritance in Man    96 CASE STUDY  To test or not to test   97 Trait Is Transmitted from Generation to Generation  76 Summary Points    97 Mendel’s First Three Postulates    76 Modern Genetic Terminology    77 Mendel’s Analytical Approach    77 Punnett Squares    78 The Testcross: One Character    79 Problems and Discussion Questions   100 3.3 Mendel’s Dihybrid Cross Generated Insights and Solutions   98 Extensions of Mendelian Genetics 104 a Unique F2 Ratio  80 4.1 Alleles Alter Phenotypes in Different Ways  105 Mendel’s Fourth Postulate: Independent Assortment    80 The Testcross: Two Characters    81 4.2 Geneticists Use a Variety of Symbols for MODE RN APPROAC HE S TO U N D E R S TA N D I N G G E N E F U N C T I O N Identifying Mendel’s Gene for Regulating White Flower Color in Peas    83 3.4 The Trihybrid Cross Demonstrates That Mendel’s Principles Apply to Inheritance of Multiple Traits  83 The Forked-Line Method, or Branch Diagram    84 A01_KLUG7260_11_GE_FM.indd 12 Alleles  106 4.3 Neither Allele Is Dominant in Incomplete, or Partial, Dominance  106 4.4 In Codominance, the Influence of Both Alleles in a Heterozygote Is Clearly Evident  107 4.5 Multiple Alleles of a Gene May Exist in a Population  108 The ABO Blood Groups    108 The A and B Antigens    108 27/08/15 4:02 PM www.downloadslide.com 13 CO N T EN T S Onset of Genetic Expression    127 Genetic Anticipation    127 Genomic (Parental) Imprinting and Gene Silencing    127 G E N E T I C S , T E C H N O L O G Y, A N D S O C I E T Y Improving the Genetic Fate of Purebred Dogs    128 CASE STUDY  But he isn’t deaf    129 Summary Points   130 Insights and Solutions   130 Problems and Discussion Questions   132 Chromosome Mapping in Eukaryotes 138 The Bombay Phenotype    109 The white Locus in Drosophila    110 4.6 Lethal Alleles Represent Essential Genes  110 The Molecular Basis of Dominance, Recessiveness, and Lethality: The agouti Gene    111 4.7 Combinations of Two Gene Pairs with Two Modes of Inheritance Modify the 9:3:3:1 Ratio  112 Evolving Concept of a Gene  112 4.8 Phenotypes Are Often Affected by More Than One Gene  113 Epistasis    114 Novel Phenotypes    117 Other Modified Dihybrid Ratios    119 4.9 Complementation Analysis Can Determine if Two Mutations Causing a Similar Phenotype Are Alleles of the Same Gene  119 4.10 Expression of a Single Gene May Have Multiple Effects  120 4.11 X-Linkage Describes Genes on the X Chromosome  121 X-Linkage in Drosophila    121 X-Linkage in Humans    122 4.12 In Sex-Limited and Sex-Influenced Inheritance, an Individual’s Sex Influences the Phenotype  123 4.13 Genetic Background and the Environment May Alter Phenotypic Expression  124 Penetrance and Expressivity    125 Genetic Background: Position Effects    125 Temperature Effects—An Introduction to Conditional Mutations    125 Nutritional Effects    126 A01_KLUG7260_11_GE_FM.indd 13 5.1 Genes Linked on the Same Chromosome Segregate Together  139 The Linkage Ratio    140 5.2 Crossing Over Serves as the Basis for Determining the Distance between Genes in Chromosome Mapping  142 Morgan and Crossing Over    142 Sturtevant and Mapping    142 Single Crossovers    144 5.3 Determining the Gene Sequence during Mapping Requires the Analysis of Multiple Crossovers  145 Multiple Exchanges    145 Three-Point Mapping in Drosophila    146 Determining the Gene Sequence    148 A Mapping Problem in Maize    150 5.4 As the Distance between Two Genes Increases, Mapping Estimates Become More Inaccurate  153 Interference and the Coefficient of Coincidence    153 5.5 Drosophila Genes Have Been Extensively Mapped  154 Evolving Concept of a Gene  154 5.6 Lod Score Analysis and Somatic Cell Hybridization Were Historically Important in Creating Human Chromosome Maps  155 5.7 Chromosome Mapping Is Now Possible Using DNA Markers and Annotated Computer Databases  157 5.8 Crossing Over Involves a Physical Exchange between Chromatids  158 5.9 Exchanges Also Occur between Sister Chromatids during Mitosis  159 27/08/15 4:02 PM www.downloadslide.com 14 CON TEN T S 5.10 Did Mendel Encounter Linkage?  160 Why Didn’t Gregor Mendel Find Linkage   160 EXPLORING GENOMICS Human Chromosome Maps on the Internet    161 CASE STUDY  Links to autism    161 Summary Points   162 Insights and Solutions   162 Problems and Discussion Questions   164 Genetic Analysis and Mapping in Bacteria and Bacteriophages 168 6.1 Bacteria Mutate Spontaneously and Grow at an Exponential Rate  169 6.2 Genetic Recombination Occurs in Bacteria  170 Conjugation in Bacteria: The Discovery of F1 and F2 Strains    170 Hfr Bacteria and Chromosome Mapping    172 Recombination in F1 F2 Matings: A Reexamination    175 The F9 State and Merozygotes    175 6.3 Rec Proteins Are Essential to Bacterial Recombination  177 6.4 The F Factor Is an Example of a Plasmid  178 6.5 Transformation Is a Second Process Leading to Genetic Recombination in Bacteria  179 The Transformation Process    179 Transformation and Linked Genes    180 6.6 Bacteriophages Are Bacterial Viruses  180 Phage T4: Structure and Life Cycle    181 The Plaque Assay    181 Lysogeny    183 6.7 Transduction Is Virus-Mediated Bacterial DNA Transfer  183 The Lederberg–Zinder Experiment    183 The Nature of Transduction    184 Transduction and Mapping    185 6.8 Bacteriophages Undergo Intergenic Recombination  185 Bacteriophage Mutations    185 Mapping in Bacteriophages   186 6.9 Intragenic Recombination Occurs in Phage T4  187 The rII Locus of Phage T4    187 Complementation by rII Mutations    188 Recombinational Analysis    188 A01_KLUG7260_11_GE_FM.indd 14 Deletion Testing of the rII Locus    189 The rII Gene Map    190 Evolving Concept of a Gene    190 G E N E T I C S , T E C H N O L O G Y, A N D S O C I E T Y From Cholera Genes to Edible Vaccines    192 CASE STUDY  To treat or not to treat    193 Summary Points   193 Insights and Solutions   193 Problems and Discussion Questions   195 Sex Determination and Sex Chromosomes  198 7.1 Life Cycles Depend on Sexual Differentiation  199 Chlamydomonas    199 Zea mays    199 Caenorhabditis elegans    201 7.2 X and Y Chromosomes Were First Linked to Sex Determination Early in the Twentieth Century  202 7.3 The Y Chromosome Determines Maleness in Humans  203 Klinefelter and Turner Syndromes    204 47,XXX Syndrome    205 47,XYY Condition    205 Sexual Differentiation in Humans    206 The Y Chromosome and Male Development    206 7.4 The Ratio of Males to Females in Humans Is Not 1.0  208 27/08/15 4:02 PM www.downloadslide.com CO N T EN T S 15 7.5 Dosage Compensation Prevents Excessive Expression of X-Linked Genes in Mammals  209 Barr Bodies    209 The Lyon Hypothesis    210 The Mechanism of Inactivation   211 7.6 The Ratio of X Chromosomes to Sets of Autosomes Determines Sex in Drosophila  213 Dosage Compensation in Drosophila    214 MODE R N APPROAC HE S TO U N D E R S TA N D I N G G E N E F U N C T I O N Drosophila Sxl Gene Induces Female Development    215 Drosophila Mosaics    216 7.7 Temperature Variation Controls 8.4 Variation Occurs in the Composition and Arrangement of Chromosomes  233 8.5 A Deletion Is a Missing Region of a Chromosome  234 Cri du Chat Syndrome in Humans    234 8.6 A Duplication Is a Repeated Segment of a Chromosome  235 Gene Redundancy and Amplification—Ribosomal RNA Genes    235 The Bar Mutation in Drosophila    236 The Role of Gene Duplication in Evolution    236 Duplications at the Molecular Level: Copy Number Variants (CNVs)    237 8.7 Inversions Rearrange the Linear Gene Sex Determination in Reptiles  216 Sequence  237 G E N E T I C S , T E C H N O L O G Y, A N D S O C I E T Y A Question of Gender: Sex Selection in Humans    218 Consequences of Inversions during Gamete Formation    238 Evolutionary Advantages of Inversions    239 CASE STUDY  Doggone it!   219 Summary Points    219 Insights and Solutions   219 Problems and Discussion Questions   220 8.8 Translocations Alter the Location of Chromosomal Segments in the Genome  239 Translocations in Humans: Familial Down Syndrome    240 8.9 Fragile Sites in Human Chromosomes Are Susceptible to Breakage  241 Chromosome Mutations: Variation in Number and Arrangement  222 8.1 Variation in Chromosome Number: Terminology and Origin  223 8.2 Monosomy and Trisomy Result in a Variety of Phenotypic Effects  223 Monosomy    223 Trisomy    224 Down Syndrome: Trisomy 21    225 The Down Syndrome Critical Region (DSCR)    226 MODE R N APPROAC HE S TO U N D E R S TA N D I N G G E N E F U N C T I O N Mouse Models of Down Syndrome   226 The Origin of the Extra 21st Chromosome in Down Syndrome    227 Human Aneuploidy    229 8.3 Polyploidy, in Which More Than Two Haploid Sets of Chromosomes Are Present, Is Prevalent in Plants  229 Autopolyploidy    230 Allopolyploidy    231 Endopolyploidy    232 A01_KLUG7260_11_GE_FM.indd 15 Fragile-X Syndrome    241 The Link between Fragile Sites and Cancer    242 G E N E T I C S , T E C H N O L O G Y, A N D S O C I E T Y Down Syndrome and Prenatal Testing—The New Eugenics?    243 CASE STUDY  Fish tales    244 Summary Points   244 Insights and Solutions   244 Problems and Discussion Questions   245 Extranuclear Inheritance  248 9.1 Organelle Heredity Involves DNA in Chloroplasts and Mitochondria  249 Chloroplasts: Variegation in Four O’Clock Plants    249 Chloroplast Mutations in Chlamydomonas    249 Mitochondrial Mutations: Early Studies in Neurospora and Yeast    250 9.2 Knowledge of Mitochondrial and Chloroplast DNA Helps Explain Organelle Heredity  252 Organelle DNA and the Endosymbiotic Theory    252 Molecular Organization and Gene Products of Chloroplast DNA    253 27/08/15 4:02 PM www.downloadslide.com 16 CON TEN T S 10.3 Evidence Favoring DNA as the Genetic Material Was First Obtained during the Study of Bacteria and Bacteriophages  267 Transformation: Early Studies    267 Transformation: The Avery, MacLeod, and McCarty Experiment    268 The Hershey–Chase Experiment    270 Transfection Experiments    271 10.4 Indirect and Direct Evidence Supports the Concept that DNA Is the Genetic Material in Eukaryotes  273 Indirect Evidence: Distribution of DNA    273 Indirect Evidence: Mutagenesis    273 Direct Evidence: Recombinant DNA Studies    273 10.5 RNA Serves as the Genetic Material in Some Viruses  274 Molecular Organization and Gene Products of Mitochondrial DNA    254 9.3 Mutations in Mitochondrial DNA Cause Human Disorders  255 Mitochondria, Human Health, and Aging    256 Future Prevention of the Transmission of mtDNA-Based Disorders    257 9.4 In Maternal Effect, the Maternal Genotype Has a Strong Influence during Early Development  258 Lymnaea Coiling    258 Embryonic Development in Drosophila    259 G E N E T I C S , T E C H N O L O G Y, A N D S O C I E T Y Mitochondrial DNA and the Mystery of the Romanovs    260 10.6 Knowledge of Nucleic Acid Chemistry Is Essential to the Understanding of DNA Structure  274 Nucleotides: Building Blocks of Nucleic Acids    274 Nucleoside Diphosphates and Triphosphates    276 Polynucleotides    276 10.7 The Structure of DNA Holds the Key to Understanding Its Function  277 Base-Composition Studies    278 X-Ray Diffraction Analysis    279 The Watson–Crick Model    279 Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid  282 Evolving Concept of a Gene    283 CASE STUDY  A twin difference    261 10.8 Alternative Forms of DNA Exist  283 Summary Points   262 10.9 The Structure of RNA Is Chemically Similar to Insights and Solutions   262 Problems and Discussion Questions   262 P art T wo DNA : S tructure , R eplication, and Variation 10 DNA Structure and Analysis  265 10.1 The Genetic Material Must Exhibit Four Characteristics  266 10.2 Until 1944, Observations Favored Protein as the Genetic Material  266 A01_KLUG7260_11_GE_FM.indd 16 DNA, but Single Stranded  284 10.10   Many Analytical Techniques Have Been Useful during the Investigation of DNA and RNA  285 Absorption of Ultraviolet Light    285 Denaturation and Renaturation of Nucleic Acids    285 Molecular Hybridization    286 Fluorescent in situ Hybridization (FISH)    286 Reassociation Kinetics and Repetitive DNA    287 Electrophoresis of Nucleic Acids    288 EXPLORING GENOMICS Introduction to Bioinformatics: BLAST    289 CASE STUDY  Zigs and zags of the smallpox virus    290 Summary Points    290 Insights and Solutions    291 Problems and Discussion Questions    292 07/09/15 3:16 PM www.downloadslide.com CO N T EN T S 17 11 DNA Replication and Recombination  295 11.1 DNA Is Reproduced by Semiconservative Replication  296 The Meselson–Stahl Experiment    297 Semiconservative Replication in Eukaryotes    298 Origins, Forks, and Units of Replication    299 11.2 DNA Synthesis in Bacteria Involves Five Polymerases, as Well as Other Enzymes  300 DNA Polymerase I    300 DNA Polymerase II, III, IV, and V    301 The DNA Pol III Holoenzyme    302 11.3 Many Complex Issues Must Be Resolved during DNA Replication  303 Unwinding the DNA Helix    303 Initiation of DNA Synthesis Using an RNA Primer    304 Continuous and Discontinuous DNA Synthesis    304 Concurrent Synthesis Occurs on the Leading and Lagging Strands    305 Proofreading and Error Correction Occurs during DNA Replication    306 11.4 A Coherent Model Summarizes DNA Replication  306 11.5 Replication Is Controlled by a Variety of Genes  307 MO DE R N APPROAC HE S TO U N D E R S TA N D I N G G E N E F U N C T I O N Lethal Knockouts of DNA Ligase Genes    307 11.6 Eukaryotic DNA Replication Is Similar to Replication in Prokaryotes, but Is More Complex  309 Initiation at Multiple Replication Origins    309 Multiple Eukaryotic DNA Polymerases    310 Replication through Chromatin    310 11.7 The Ends of Linear Chromosomes Are Problematic during Replication  311 Telomere Structure    311 Replication at the Telomere    311 11.8 DNA Recombination, Like DNA Replication, Is Directed by Specific Enzymes  313 Models of Homologous Recombination    313 Enzymes and Proteins Involved in Homologous Recombination    315 Gene Conversion, a Consequence of Homologous Recombination    315 A01_KLUG7260_11_GE_FM.indd 17 G E N E T I C S , T E C H N O L O G Y, A N D S O C I E T Y Telomeres: The Key to Immortality?    317 CASE STUDY  At loose ends    318 Summary Points   318 Insights and Solutions   318 Problems and Discussion Questions   319 12 DNA Organization in Chromosomes  322 12.1 Viral and Bacterial Chromosomes Are Relatively Simple DNA Molecules  323 12.2 Supercoiling Facilitates Compaction of the DNA of Viral and Bacterial Chromosomes  324 12.3 Specialized Chromosomes Reveal Variations in the Organization of DNA  326 Polytene Chromosomes    326 Lampbrush Chromosomes    327 12.4 DNA Is Organized into Chromatin in Eukaryotes  328 Chromatin Structure and Nucleosomes    328 Chromatin Remodeling    330 Heterochromatin    332 12.5 Chromosome Banding Differentiates Regions along the Mitotic Chromosome  332 12.6 Eukaryotic Genomes Demonstrate Complex Sequence Organization Characterized by Repetitive DNA  334 Satellite DNA    334 Centromeric DNA Sequences    335 Middle Repetitive Sequences: VNTRs and STRs    335 Repetitive Transposed Sequences: SINEs and LINEs    336 Middle Repetitive Multiple-Copy Genes    336 12.7 The Vast Majority of a Eukaryotic Genome Does Not Encode Functional Genes  336 EXPLORING GENOMICS Database of Genomic Variants: Structural Variations in the Human Genome    337 Case Study  Art inspires learning    338 Summary Points   338 Insights and Solutions   338 Problems and Discussion Questions   339 07/09/15 3:16 PM www.downloadslide.com 18 CON TEN T S Pa rt T h ree Gene E xp re ssion, Reg u lation, and Develo pment 13 The Genetic Code and Transcription  342 13.1 The Genetic Code Uses Ribonucleotide Bases as “Letters”  343 13.2 Early Studies Established the Basic Operational Patterns of the Code  343 The Triplet Nature of the Code    344 The Nonoverlapping Nature of the Code    344 The Commaless and Degenerate Nature of the Code    345 13.3 Studies by Nirenberg, Matthaei, and Others Led to Deciphering of the Code  345 Synthesizing Polypeptides in a Cell-Free System    345 Homopolymer Codes    346 Mixed Copolymers    346 The Triplet-Binding Assay    347 Repeating Copolymers    349 13.4 The Coding Dictionary Reveals Several Interesting Patterns among the 64 Codons  350 Degeneracy and the Wobble Hypothesis    350 The Ordered Nature of the Code    351 Initiation, Termination, and Suppression    351 13.5 The Genetic Code Has Been Confirmed in Studies of Phage MS2  352 13.6 The Genetic Code Is Nearly Universal  352 13.9 Studies with Bacteria and Phages Provided Evidence for the Existence of mRNA  354 13.10     RNA Polymerase Directs RNA Synthesis  355 Promoters, Template Binding, and the s Subunit    356 Initiation, Elongation, and Termination of RNA Synthesis    357 13.11    Transcription in Eukaryotes Differs from Prokaryotic Transcription in Several Ways  357 Initiation of Transcription in Eukaryotes    358 Recent Discoveries Concerning RNA Polymerase Function    359 Processing Eukaryotic RNA: Caps and Tails    360 13.12    The Coding Regions of Eukaryotic Genes Are Interrupted by Intervening Sequences Called Introns  360 Splicing Mechanisms: Self-Splicing RNAs    362 Splicing Mechanisms: The Spliceosome    362 Evolving Concept of a Gene    363 13.13    RNA Editing May Modify the Final Transcript  364 13.14    Transcription Has Been Visualized by Electron Microscopy  364 Case Study  A drug that sometimes works    365 Summary Points    365 G E N E T I C S , T E C H N O L O G Y, A N D S O C I E T Y Fighting Disease with Antisense Therapeutics    366 Insights and Solutions   367 Problems and Discussion Questions   367 13.7 Different Initiation Points Create Overlapping Genes  353 13.8 Transcription Synthesizes RNA on a DNA Template  354 14 Translation and Proteins  371 14.1 Translation of mRNA Depends on Ribosomes and Transfer RNAs  371 Ribosomal Structure    372 tRNA Structure    373 Charging tRNA    374 14.2 Translation of mRNA Can Be Divided into Three Steps  375 Initiation    376 Elongation    376 Termination    378 Polyribosomes    378 14.3 High-Resolution Studies Have Revealed Many Details about the Functional Prokaryotic Ribosome  379 A01_KLUG7260_11_GE_FM.indd 18 27/08/15 4:02 PM www.downloadslide.com CO N T EN T S 19 14.4 Translation Is More Complex in Eukaryotes  380 14.5 The Initial Insight That Proteins Are Important in Heredity Was Provided by the Study of Inborn Errors of Metabolism  381 Phenylketonuria    382 14.6 Studies of Neurospora Led to the One-Gene:One- Enzyme Hypothesis  382 Analysis of Neurospora Mutants by Beadle and Tatum    382 Genes and Enzymes: Analysis of Biochemical Pathways    384 14.7 Studies of Human Hemoglobin Established That One Gene Encodes One Polypeptide  385 Sickle-Cell Anemia    385 Human Hemoglobins    387 Evolving Concept of the Gene    387 14.8 The Nucleotide Sequence of a Gene and the Amino Acid Sequence of the Corresponding Protein Exhibit Colinearity  387 14.9 Variation in Protein Structure Provides the Basis of Biological Diversity  388 14.10 Posttranslational Modification Alters the Final Protein Product  391 Protein Folding and Misfolding    392 14.11 Proteins Function in Many Diverse Roles  393 14.12 Proteins Are Made Up of One or More Functional Domains  394 Exon Shuffling    394 The Origin of Protein Domains    395 EXPLORING GENOMICS Translation Tools and Swiss-Prot for Studying Protein Sequences    395 Case Study  Crippled ribosomes    396 Summary Points    397 Insights and Solutions    397 Problems and Discussion Questions    397 15 Gene Mutation, DNA Repair, and Transposition  401 15.1 Gene Mutations Are Classified in Various Ways  402 Classification Based on Type of Molecular Change    402 Classification Based on Phenotypic Effects    403 Classification Based on Location of Mutation    404 A01_KLUG7260_11_GE_FM.indd 19 15.2 Mutations Occur Spontaneously and Randomly  404 Spontaneous and Induced Mutations    404 Spontaneous Mutation Rates in Humans    405 The Fluctuation Test: Are Mutations Random or Adaptive?    405 15.3 Spontaneous Mutations Arise from Replication Errors and Base Modifications  407 DNA Replication Errors and Slippage    407 Tautomeric Shifts    407 Depurination and Deamination    408 Oxidative Damage    408 Transposable Elements    409 15.4 Induced Mutations Arise from DNA Damage Caused by Chemicals and Radiation  409 Base Analogs    409 Alkylating, Intercalating, and Adduct-Forming Agents    409 Ultraviolet Light    410 Ionizing Radiation    411 15.5 Single-Gene Mutations Cause a Wide Range of Human Diseases  412 Single Base-Pair Mutations and b-Thalassemia    413 Mutations Caused by Expandable DNA Repeats    413 15.6 Organisms Use DNA Repair Systems to Counteract Mutations  414 Proofreading and Mismatch Repair    414 Postreplication Repair and the SOS Repair System    415 Photoreactivation Repair: Reversal of UV Damage    415 Base and Nucleotide Excision Repair    415 Nucleotide Excision Repair and Xeroderma Pigmentosum in Humans    417 Double-Strand Break Repair in Eukaryotes    418 15.7 The Ames Test Is Used to Assess the Mutagenicity of Compounds  419 15.8 Transposable Elements Move within the Genome and May Create Mutations  420 Insertion Sequences and Bacterial Transposons    420 The Ac–Ds System in Maize    421 Copia and P Elements in Drosophila    422 Transposable Elements in Humans    422 M O D E R N A P P R O A C H E S TO U N D E R S TA N D I N G G E N E F U N C T I O N Transposon-Mediated Mutations Reveal Genes Involved in Colorectal Cancer    423 Transposons, Mutations, and Evolution    424 27/08/15 4:02 PM www.downloadslide.com 20 CON TEN T S EXPLORING GENOMICS Sequence Alignment to Identify a Mutation    425 Case Study  Genetic dwarfism    425 Summary Points   426 Insights and Solutions   426 Problems and Discussion Questions   427 16 Regulation of Gene Expression in Prokaryotes  430 16.1 Prokaryotes Regulate Gene Expression in Response to Environmental Conditions  431 16.2 Lactose Metabolism in E coli Is Regulated by an Inducible System  431 Structural Genes    432 The Discovery of Regulatory Mutations    433 The Operon Model: Negative Control    433 Genetic Proof of the Operon Model    433 Isolation of the Repressor    435 17 Regulation of Gene Expression in Eukaryotes  451 17.1 Eukaryotic Gene Regulation Can Occur at Any of the Steps Leading from DNA to Protein Product  452 17.2 Eukaryotic Gene Expression Is Influenced by Chromatin Modifications  453 Chromosome Territories and Transcription Factories    453 Open and Closed Chromatin    453 Histone Modifications and Nucleosomal Chromatin Remodeling    454 DNA Methylation    454 17.3 Eukaryotic Transcription Initiation Requires Specific Cis-Acting Sites  455 Promoter Elements    455 Enhancers and Silencers    456 17.4 Eukaryotic Transcription Initiation Is Regulated by Transcription Factors That Bind to Cis-Acting Sites  458 The Human Metallothionein IIA Gene: Multiple Cis-Acting Elements and Transcription Factors    458 Functional Domains of Eukaryotic Transcription Factors    459 16.3 The Catabolite-Activating Protein (CAP) Exerts 17.5 Activators and Repressors Interact with General Positive Control over the lac Operon  436 Transcription Factors and Affect Chromatin Structure  459 16.4 Crystal Structure Analysis of Repressor Complexes Has Confirmed the Operon Model  438 16.5 The Tryptophan (trp) Operon in E coli Is a Repressible Gene System  440 Evidence for the trp Operon    440 Evolving Concept of the Gene    440 16.6 Alterations to RNA Secondary Structure Contribute to Prokaryotic Gene Regulation  441 Attenuation    442 Riboswitches    443 16.7 The ara Operon Is Controlled by a Regulator Protein That Exerts Both Positive and Negative Control  444 Case Study Food poisoning and bacterial gene expression    445 Summary Points    445 G E N E T I C S , T E C H N O L O G Y, A N D S O C I E T Y Quorum Sensing: Social Networking in the Bacterial World    446 Insights and Solutions   447 Problems and Discussion Questions   447 A01_KLUG7260_11_GE_FM.indd 20 Formation of the RNA Polymerase II Transcription Initiation Complex    459 Mechanisms of Transcription Activation and Repression    460 17.6 Gene Regulation in a Model Organism: Transcription of the GAL Genes of Yeast  461 17.7 Posttranscriptional Gene Regulation Occurs at Many Steps from RNA Processing to Protein Modification  462 Alternative Splicing of mRNA    463 Alternative Splicing and Human Diseases    464 Sex Determination in Drosophila: A Model for Regulation of Alternative Splicing    464 Control of mRNA Stability    466 Translational and Posttranslational Regulation    466 17.8 RNA Silencing Controls Gene Expression in Several Ways  466 The Molecular Mechanisms of RNA-Induced Gene Silencing    467 RNA-Induced Gene Silencing in Biotechnology and Medicine    468 MODERN APPROACHES TO U N D E R S TA N D I N G G E N E F U N C T I O N MicroRNAs Regulate Ovulation in Female Mice    469 27/08/15 4:02 PM www.downloadslide.com 21 CO N T EN T S 18.5 Homeotic Selector Genes Specify Body Parts of the Adult  486 Hox Genes in Drosophila    486 Hox Genes and Human Genetic Disorders    488 18.6 Plants Have Evolved Developmental Regulatory Systems That Parallel Those of Animals  489 Homeotic Genes in Arabidopsis    489 Evolutionary Divergence in Homeotic Genes    490 18.7 C elegans Serves as a Model for Cell–Cell Interactions in Development  491 Signaling Pathways in Development    491 M O D E R N A P P R O A C H E S TO U N D E R S TA N D I N G G E N E F U N C T I O N Single-Gene Signaling Mechanism Reveals Secrets to Head Regeneration in Planaria    492 17.9 Programmed DNA Rearrangements Regulate Expression of a Small Number of Genes  470 The Notch Signaling Pathway    493 Overview of C elegans Development    493 Genetic Analysis of Vulva Formation    494 The Immune System and Antibody Diversity    470 Gene Rearrangements in the k Light-Chain Gene    471 17.10 ENCODE Data Are Transforming Our Concepts of Eukaryotic Gene Regulation  472 Enhancer and Promoter Elements    472 Transcripts and RNA Processing    473 18.8 Binary Switch Genes and Signaling Pathways Program Genomic Expression  496 The Control of Eye Formation    496 EXPLORING GENOMICS Tissue-Specific Gene Expression    473 G E N E T I C S , T E C H N O L O G Y, A N D S O C I E T Y Stem Cell Wars    498 Case Study  A mysterious muscular dystrophy    474 Case Study  One foot or another    499 Summary Points   474 Summary Points   499 Insights and Solutions   475 Insights and Solutions   500 Problems and Discussion Questions   476 Problems and Discussion Questions    500 18 Developmental Genetics 479 18.1 Differentiated States Develop from Coordinated Programs of Gene Expression  479 19 Cancer and Regulation of the Cell Cycle  503 19.1 Cancer Is a Genetic Disease at the Level of Somatic Cells  504 18.2 Evolutionary Conservation of Developmental What Is Cancer?    504 The Clonal Origin of Cancer Cells    504 The Cancer Stem Cell Hypothesis    505 Mechanisms Can Be Studied Using Model Organisms  480 Analysis of Developmental Mechanisms    481 18.3 Genetic Analysis of Embryonic Development in Drosophila Reveals How the Body Axis of Animals Is Specified  481 Overview of Drosophila Development    481 Genetic Analysis of Embryogenesis    482 18.4 Zygotic Genes Program Segment Formation in Drosophila  484 Gap Genes    484 Pair-Rule Genes    484 Segment Polarity Genes    484 Segmentation Genes in Mice and Humans    485 A01_KLUG7260_11_GE_FM.indd 21 13 19 14 20 15 10 11 12 16 17 18 21 22 x 27/08/15 4:02 PM www.downloadslide.com 22 CON TEN T S Cancer as a Multistep Process, Requiring Multiple Mutations    505 Driver Mutations and Passenger Mutations    506 19.2 Cancer Cells Contain Genetic Defects Affecting Genomic Stability, DNA Repair, and Chromatin Modifications  506 Genomic Instability and Defective DNA Repair    507 Chromatin Modifications and Cancer Epigenetics    508 19.3 Cancer Cells Contain Genetic Defects Affecting Cell-Cycle Regulation  508 The Cell Cycle and Signal Transduction    508 Cell-Cycle Control and Checkpoints    509 Control of Apoptosis    510 19.4 Proto-oncogenes and Tumor-Suppressor Genes Are Altered in Cancer Cells  510 The ras Proto-oncogenes    512 The p53 Tumor-Suppressor Gene    512 The RB1 Tumor-Suppressor Gene    513 19.5 Cancer Cells Metastasize and Invade Other Tissues  515 19.6 Predisposition to Some Cancers Can Be Inherited  516 19.7 Viruses Contribute to Cancer in Both Humans and Animals  516 19.8 Environmental Agents Contribute to Human Cancers  518 EXPLORING GENOMICS The Cancer Genome Anatomy Project (CGAP)    519 Case Study  I thought it was safe    519 Summary Points    519 Insights and Solutions    520 Problems and Discussion Questions    486  DNA Vectors Accept and Replicate DNA Molecules to Be Cloned    525 Bacterial Plasmid Vectors    526 Other Types of Cloning Vectors    528 Ti Vectors for Plant Cells    529 Host Cells for Cloning Vectors    529 20.2 DNA Libraries Are Collections of Cloned Sequences  530 Genomic Libraries    530 Complementary DNA (cDNA) Libraries    530 Specific Genes Can Be Recovered from a Library by Screening    531 20.3 The Polymerase Chain Reaction Is a Powerful Technique for Copying DNA  532 Limitations of PCR    535 Applications of PCR    536 20.4 Molecular Techniques for Analyzing DNA  537 Restriction Mapping    537 Nucleic Acid Blotting    538 20.5 DNA Sequencing Is the Ultimate Way to Characterize DNA Structure at the Molecular Level  541 Sequencing Technologies Have Progressed Rapidly    543 Next-Generation and Third-Generation Sequencing Technologies    543 DNA Sequencing and Genomics    545 20.6 Creating Knockout and Transgenic Organisms for Studying Gene Function  545 Gene Targeting and Knockout Animal Models    545 Making a Transgenic Animal: The Basics    549 EXPLORING GENOMICS Manipulating Recombinant DNA: Restriction Mapping and Designing PCR Primers    550 Case Study Should we worry about recombinant DNA technology?    551 Summary Points    551 Insights and Solutions   552 Par t Fou r G enomic s 20 Recombinant DNA Technology  523 20.1 Recombinant DNA Technology Began with Two Key Tools: Restriction Enzymes and DNA Cloning Vectors  524 Restriction Enzymes Cut DNA at Specific Recognition Sequences    524 A01_KLUG7260_11_GE_FM.indd 22 Problems and Discussion Questions   552 21 Genomics, Bioinformatics, and Proteomics  556 21.1 Whole-Genome Sequencing Is a Widely Used Method for Sequencing and Assembling Entire Genomes  557 High-Throughput Sequencing and Its Impact on Genomics    558 The Clone-by-Clone Approach    559 Draft Sequences and Checking for Errors    561 27/08/15 4:02 PM www.downloadslide.com 23 CO N T EN T S Comparative Genomics Provides Novel Information about the Genomes of Model Organisms and the Human Genome    580 The Sea Urchin Genome    580 The Dog Genome    581 The Chimpanzee Genome    581 The Rhesus Monkey Genome    582 The Neanderthal Genome and Modern Humans    582 21.7 Comparative Genomics Is Useful for Studying the Evolution and Function of Multigene Families  583 21.8 Metagenomics Applies Genomics Techniques to Environmental Samples  585 21.9 Transcriptome Analysis Reveals Profiles of 21.2 DNA Sequence Analysis Relies on Bioinformatics Applications and Genome Databases  561 Annotation to Identify Gene Sequences    562 Hallmark Characteristics of a Gene Sequence Can Be Recognized during Annotation    563 21.3 Genomics Attempts to Identify Potential Functions of Genes and Other Elements in a Genome  565 Predicting Gene and Protein Functions by Sequence Analysis    565 Predicting Function from Structural Analysis of Protein Domains and Motifs    566 Investigators Are Using Genomics Techniques Such as Chromatin Immunoprecipitation to Investigate Aspects of Genome Function and Regulation    566 21.4 The Human Genome Project Revealed Many Important Aspects of Genome Organization in Humans  567 Origins of the Project    568 Major Features of the Human Genome    568 Individual Variations in the Human Genome    569 Accessing the Human Genome Project on the Internet    570 21.5 The “Omics” Revolution Has Created a New Era of Biological Research  572 Stone-Age Genomics    572 After the HGP: What Is Next?    573 Personal Genome Projects and Personal Genomics    573 Exome Sequencing    575 Encyclopedia of DNA Elements (ENCODE) Project    575 Evolving Concept of a Gene    576 The Human Microbiome Project    576 No Genome Left Behind and the Genome 10K Plan    577 21.6 Comparative Genomics Analyzes and Compares Genomes from Different Organisms  578 Prokaryotic and Eukaryotic Genomes Display Common Structural and Functional Features and Important Differences    578 A01_KLUG7260_11_GE_FM.indd 23 Expressed Genes in Cells and Tissues  587 Microarray Analysis    587 21.10 Proteomics Identifies and Analyzes the Protein Composition of Cells  590 Reconciling the Number of Genes and the Number of Proteins Expressed by a Cell or Tissue    590 Proteomics Technologies: Two-Dimensional Gel Electrophoresis for Separating Proteins    591 Proteomics Technologies: Mass Spectrometry for Protein Identification    592 Identification of Collagen in Tyrannosaurus rex and Mammut americanum Fossils    595 21.11 Systems Biology Is an Integrated Approach to Studying Interactions of All Components of an Organism’s Cells  596 EXPLORING GENOMICS Contigs, Shotgun Sequencing, and Comparative Genomics    598 Case Study Your microbiome may be a risk factor for disease    599 Summary Points   599 Insights and Solutions   600 Problems and Discussion Questions   600 22 Applications and Ethics of Genetic Engineering and Biotechnology  603 22.1 Genetically Engineered Organisms Synthesize a Wide Range of Biological and Pharmaceutical Products  604 Insulin Production in Bacteria    604 Transgenic Animal Hosts and Pharmaceutical Products    605 27/08/15 4:02 PM www.downloadslide.com 24 CON TEN T S Recombinant DNA Approaches for Vaccine Production    607 Vaccine Proteins Can Be Produced by Plants    607 DNA-Based Vaccines    607 22.2 Genetic Engineering of Plants Has Revolutionized Case Study  Cancer-killing bacteria    634 Summary Points   634 Insights and Solutions   634 Problems and Discussion Questions   635 Agriculture  608 22.3 Transgenic Animals Serve Important Roles In Biotechnology  609 Examples of Transgenic Animals    609 22.4 Synthetic Genomes and the Emergence of Synthetic Biology  610 How Simple Can a Genome Be?    610 Transplantation of a Synthetic Genome    611 Synthetic Biology for Bioengineering Applications    613 22.5 Genetic Engineering and Genomics Are Transforming Medical Diagnosis  614 Prenatal Genetic Testing    614 Genetic Tests Based on Restriction Enzyme Analysis    616 Genetic Testing Using Allele-Specific Oligonucleotides    617 Genetic Testing Using DNA Microarrays and Genome Scans    619 Genetic Analysis Using Gene-Expression Microarrays    621 Application of Microarrays for Gene Expression and Genotype Analysis of Pathogens    623 22.6 Genetic Analysis by Individual Genome Sequencing  625 22.7 Genome-Wide Association Studies Identify Genome Variations That Contribute to Disease  626 22.8 Genomics Leads to New, More Targeted Medical Treatment Including Personalized Medicine  627 Pharmacogenomics and Rational Drug Design    627 Gene Therapy    629 22.9 Genetic Engineering, Genomics, and Biotechnology Create Ethical, Social, and Legal Questions  629 Par t Five Genetics o f O rgani s ms and Population s 23 Quantitative Genetics and Multifactorial Traits  638 23.1 Not All Polygenic Traits Show Continuous Variation  639 23.2 Quantitative Traits Can Be Explained in Mendelian Terms  639 The Multiple-Gene Hypothesis for Quantitative Inheritance    639 Additive Alleles: The Basis of Continuous Variation    640 Calculating the Number of Polygenes    641 23.3 The Study of Polygenic Traits Relies on Statistical Analysis  642 The Mean    642 Variance    643 Standard Deviation    643 Standard Error of the Mean    643 Covariance and Correlation Coefficient    643 Analysis of a Quantitative Character    644 23.4 Heritability Values Estimate the Genetic Contribution to Phenotypic Variability  645 Broad-Sense Heritability    646 Narrow-Sense Heritability    646 Artificial Selection    647 23.5 Twin Studies Allow an Estimation of Heritability in Humans  648 Twin Studies Have Several Limitations    649 Genetic Testing and Ethical Dilemmas    629 Direct-to-Consumer Genetic Testing and Regulating the Genetic Test Providers    630 DNA and Gene Patents    631 Whole Genome Sequence Analysis Presents Many Questions of Ethics    632 Preconception Testing, Destiny Predictions, and BabyPredicting Patents    632 Patents and Synthetic Biology    632 23.6 Quantitative Trait Loci Are Useful in Studying G E N E T I C S , T E C H N O L O G Y, A N D S O C I E T Y Privacy and Anonymity in the Era of Genomic Big Data    633 Insights and Solutions   654 A01_KLUG7260_11_GE_FM.indd 24 Multifactorial Phenotypes  650 Expression QTLs (eQTLs) and Genetic Disorders    652 G E N E T I C S , T E C H N O L O G Y, A N D S O C I E T Y The Green Revolution Revisited: Genetic Research with Rice    653 Case Study  A genetic flip of the coin    654 Summary Points   654 Problems and Discussion Questions   655 27/08/15 4:02 PM www.downloadslide.com 25 CO N T EN T S 24 Neurogenetics  659 24.1 The Central Nervous System Receives Sensory Input and Generates Behavioral Responses  660 Organization of Cells in the Central Nervous System    660 Synapses Transfer Information between Neurons    661 24.2 Identification of Genes Involved in Transmission of Nerve Impulses  662 24.3 Synapses Are Involved in Many Human Behavioral Disorders  664 A Defect in Neurotransmitter Breakdown    664 Fragile-X Syndrome and Synapses    665 24.4 Animal Models Play an Important Role in the Study of Huntington Disease and Learning Behavior  666 Huntington Disease Is a Neurodegenerative Behavioral Disorder    666 A Transgenic Mouse Model of Huntington Disease    667 Mechanism of Huntington Disease    667 Treatment Strategies for Huntington Disease    668 Drosophila as an Animal Model for Learning and Memory    669 Dissecting the Mechanisms and Neural Pathways in Learning    669 Drosophila Is an Effective Model for Learning and Memory in Humans    670 24.5 Behavioral Disorders Have Environmental Components  670 MO DE R N APPROAC HE S TO U N D E R S TA N D I N G G E N E F U N C T I O N RbAp48 and a Potential Molecular Mechanism for Age-Related Memory Loss    671 Schizophrenia Is a Complex Behavioral Disorder    672 Several Behavioral Disorders Share a Genetic Relationship    673 Epigenetics and Mental Illness    674 Addiction and Alcoholism Are Behaviors with Genetic and Environmental Causes    675 Case Study Primate models for human disorders    677 EXPLORING GENOMICS HomoloGene: Searching for Behavioral Genes    677 Summary Points    678 Insights and Solutions    678 Problems and Discussion Questions    678 25 Population and Evolutionary Genetics  681 25.1 Genetic Variation Is Present in Most Populations and Species  682 Detecting Genetic Variation by Artificial Selection    682 Variations in Nucleotide Sequence    682 Explaining the High Level of Genetic Variation in Populations    683 25.2 The Hardy–Weinberg Law Describes Allele Frequencies and Genotype Frequencies in Populations  684 25.3 The Hardy–Weinberg Law Can Be Applied to Human Populations  686 Testing for Hardy–Weinberg Equilibrium in a Population    687 Calculating Frequencies for Multiple Alleles in Populations    688 Calculating Allele Frequencies for X-linked Traits    689 Calculating Heterozygote Frequency    689 25.4 Natural Selection Is a Major Force Driving Allele Frequency Change  689 Detecting Natural Selection in Populations    690 Fitness and Selection    690 There Are Several Types of Selection    691 25.5 Mutation Creates New Alleles in a Gene Pool  692 25.6 Migration and Gene Flow Can Alter Allele Frequencies  693 25.7 Genetic Drift Causes Random Changes in Allele Frequency in Small Populations  694 Founder Effects in Human Populations    694 25.8 Nonrandom Mating Changes Genotype Frequency but Not Allele Frequency  695 Inbreeding    696 A01_KLUG7260_11_GE_FM.indd 25 27/08/15 4:02 PM www.downloadslide.com 26 CON TEN T S 25.9 Reduced Gene Flow, Selection, and Genetic Drift Can Lead to Speciation  696 Changes Leading to Speciation    697 The Rate of Macroevolution and Speciation    697 25.10     Phylogeny Can Be Used to Analyze Evolutionary History  698 Constructing Phylogenetic Trees from Amino Acid Sequences    699 Molecular Clocks Measure the Rate of Evolutionary Change    699 Genomics and Molecular Evolution    699 The Complex Origins of Our Genome    699 Our Genome Is a Mosaic    702 BOX 1  RNA-Guided Gene Therapy with CRISPR/Cas Technology    724 Summary Points    704 Insights and Solutions    704 BOX 2  Do Extracellular RNAs Play Important Roles in Cellular Communication?    731 Problems and Discussion Questions    705 Epigenetics 708 Epigenetic Alterations to the Genome  709 DNA Forensics 735 BOX   The Beginning of Epigenetics    709 BOX 1  The Pitchfork Case: The First Criminal Conviction Using DNA Profiling    736 Assisted Reproductive Technologies (ART) and Imprinting Defects  713 Epigenetics and Cancer  713 Epigenetics and the Environment  715 Autosomal STR DNA Profiling   737 Y-Chromosome STR Profiling   738 Mitochondrial DNA Profiling   739 BOX 2  Thomas Jefferson’s DNA: Paternity and Beyond    740 BOX   What More We Need to Know about Epigenetics and Cancer    715 Epigenome Projects  716 DNA Profiling Methods  735 VNTR-Based DNA Fingerprinting    735 Epigenetics and Imprinting  711 mRNA Localization and Translational Regulation in Eukaryotes  732 SPECIAL TOPICS IN MODERN GENETICS DNA Methylation   709 Histone Modification and Chromatin Remodeling   710 MicroRNAs and Long Noncoding RNAs   710 Long Noncoding RNAs Are Abundant and Have Diverse Functions    728 lncRNAs Mediate Transcriptional Repression by Interacting with Chromatin-Regulating Complexes    728 lncRNAs Regulate Transcription Factor Activity    729 Circular RNAs Act as “Sponges” to Soak Up MicroRNAs    729 Case Study  An unexpected outcome    703 Small Noncoding RNAs Mediate the Regulation of Eukaryotic Gene Expression    724 siRNAs and RNA Interference    725 miRNAs Regulate Posttranscriptional Gene Expression    726 piRNAs Protect the Genome for Future Generations    726 RNA-Induced Transcriptional Silencing    727 G E N E T I C S , T E C H N O L O G Y, A N D S O C I E T Y Tracking Our Genetic Footprints out of Africa    702 Special Topics In Modern Genetics Prokaryotes Have an RNA-Guided Viral Defense Mechanism    722 Single-Nucleotide Polymorphism Profiling   740 Interpreting DNA Profiles  741 BOX 3  The Pascal Della Zuana Case: DNA Barcodes and Wildlife Forensics    741 Special Topics In Modern Genetics The Uniqueness of DNA Profiles   742 The Prosecutor’s Fallacy    743 DNA Profile Databases    743 Emerging Roles of RNA 718 Genetic Engineering of Ribozymes    720 BOX 4  The Kennedy Brewer Case: Two Bite-Mark Errors and One Hit    743 Catalytic Activity of RNAs: Ribozymes and the Origin of Life  718 Small Noncoding RNAs Play Regulatory Roles in Prokaryotes    721 A01_KLUG7260_11_GE_FM.indd 26 Technical and Ethical Issues Surrounding DNA Profiling  744 BOX 5  A Case of Transference: The Lukis Anderson Story    744 27/08/15 4:02 PM www.downloadslide.com CO N T EN T S 27 SPECIAL TOPICS IN MODERN GENETICS Genomics and Personalized Medicine  746 Personalized Medicine and Pharmacogenomics  746 Optimizing Drug Therapies    747 SPECIAL TOPICS IN MODERN GENETICS Gene Therapy 772 BOX 1  The Story of Pfizer’s Crizotinib    747 Personalized Medicine and Disease Diagnostics  750 BOX 2  The Pharmacogenomics Knowledge Base (PharmGKB): Genes, Drugs, and Diseases on the Web    751 Personal Genomics and Cancer    752 BOX 1  ClinicalTrials.gov    774 Nonviral Delivery Methods    776 The First Successful Gene Therapy Trial  776 Gene Therapy Setbacks  777 Problems with Gene Therapy Vectors    778 BOX 2  Glybera Is the First Commercial Gene Therapy to Be Approved in the West    780 Personal Genomics and Disease Diagnosis: Analyzing One Genome    753 Technical, Social, and Ethical Challenges  754 Genetically Modified Foods 758 What Are GM Foods?  759 Targeted Approaches to Gene Therapy  781 DNA-Editing Nucleases for Gene Targeting    781 RNA Silencing for Gene Inhibition    782 BOX Beyond Genomics: Personal Omics Profiling    755 SPECIAL TOPICS IN MODERN GENETICS Recent Successful Trials  778 Treating Retinal Blindness    778 HIV as a Vector Shows Promise in Recent Trials    779 BOX 3  Personalized Cancer Diagnostics and Treatments: The Lukas Wartman Story    753 How Are Therapeutic Genes Delivered?  773 Viral Vectors for Gene Therapy    773 Reducing Adverse Drug Reactions 749 What Genetic Conditions Are Candidates for Treatment by Gene Therapy?  772 Future Challenges and Ethical Issues  784 Ethical Concerns Surrounding Gene Therapy    784 BOX 3  Gene Doping for Athletic Performance?    784 Appendix A   Selected Readings   787 Appendix B   Answers to Selected Problems   799 Herbicide-Resistant GM Crops    759 Insect-Resistant GM Crops    760 Glossary  841 BOX 1  The Tale of GM Salmon—Downstream Effects?    760 Index  867 Credits  863 Insect-Resistant GM Crops    760 GM Crops for Direct Consumption    761 BOX 2  The Monarch Butterfly Story    762 BOX 3  The Success of Hawaiian GM Papaya    763 Methods Used to Create GM Plants  763 Selectable Markers    765 Roundup-Ready® Soybeans    765 Golden Rice    766 GM Foods Controversies  766 Health and Safety    767 Environmental Effects    768 The Future of GM Foods  769 A01_KLUG7260_11_GE_FM.indd 27 27/08/15 4:02 PM www.downloadslide.com Preface It is essential that textbook authors step back and look with fresh eyes as each edition of their work is planned In doing so, two main questions must be posed: (1) How has the body of information in their field—in this case Genetics—grown and shifted since the last edition; and (2) What pedagogic innovations might be devised and incorporated into the text that will unquestionably enhance students’ learning? The preparation of the 11th edition of Concepts of Genetics, a text now entering its fourth decade of providing support for students studying in this field, has occasioned still another fresh look And what we focused on in this new edition, in addition to the normal updating that is inevitably required, were two things: (1) the need to increase the opportunities for instructors and students to engage in active and cooperative learning approaches, either within or outside of the classroom; and (2) the need to provide more comprehensive coverage of important, emerging topics that not yet warrant their own traditional chapters Regarding the first point, and as discussed in further detail below, we have added a new feature called Modern Understanding of Gene Function, which appears within many chapters In addition, we have retained the very popular Genetics, Technology, and Society essays that appear at the end of many chapters This feature includes an active learning format called Your Turn, which directly engages the student with provocative assignments These features are in addition to Exploring Genomics entries, and together, these all may serve as the basis for interactions between small groups of students, either in or out of the classroom Regarding emerging topics, we continue to include a unique approach in genetics textbooks that offers readers a set of abbreviated, highly focused chapters that we label Special Topics in Modern Genetics In this edition, these provide uniquely cohesive coverage of six important topics: Epigenetics, Emerging Roles of RNA, Genomics and Personalized Medicine, DNA Forensics, Genetically Modified Foods, and Gene Therapy Three of these (RNA, GM Foods, and Gene Therapy) are new to this edition ■ ■ ■ ■ ■ Emphasize the basic concepts of genetics Maintain our strong emphasis on and provide multiple approaches to problem solving Propagate the rich history of genetics, which so beautifully illustrates how information is acquired during scientific investigation Create inviting, engaging, and pedagogically useful fullcolor figures enhanced by equally helpful photographs to support concept development These goals collectively serve as the cornerstone of Concepts of Genetics This pedagogic foundation allows the book to be used in courses with many different approaches and lecture formats Writing a textbook that achieves these goals and having the opportunity to continually improve on each new edition has been a labor of love for us The creation of each of the eleven editions is a reflection not only of our passion for teaching genetics, but also of the constructive feedback and encouragement provided by adopters, reviewers, and our students over the past three decades New to This Edition ■ Goals In the 11th edition of Concepts of Genetics, as in all past editions, we have five major goals Specifically, we have sought to: Write clearly and directly to students in order to provide understandable explanations of complex, analytical topics ■ Special Topics in Modern Genetics—We have been pleased with the popular reception that the Special Topics in Modern Genetics chapters has received First introduced in the tenth edition, our goal has been to provide abbreviated, cohesive coverage of important topics in genetics that are not always easily located in textbooks Professors have used these focused, flexible chapters as the backbone of lectures, as inspiration for student assignments outside of class, and as the basis of group assignments and presentations New to this edition are chapters on topics of great significance in genetics: Emerging Roles of RNA, Genetically Modified Foods, and Gene Therapy For all Special Topic chapters, we have added a series of questions that send the student back into the chapter to review key ideas or provide the basis of personal contemplations and group discussions Modern Approaches to Understanding Gene Function This new feature highlights how advances in genetic technology have led to our modern understanding of gene 28 A01_KLUG7260_11_GE_FM.indd 28 27/08/15 4:02 PM www.downloadslide.com P reface 29 function Appearing in many chapters, this feature also prompts students to apply their analytical thinking skills, linking the experimental technology to the findings that enhance our understanding of gene function ■ ■ ■ ■ Evolving Concept of the Gene Also new to this edition is a short feature, integrated in appropriate chapters, that highlights how scientists’ understanding of what a gene is has changed over time Since we cannot see genes, we must infer just what this unit of heredity is, based on experimental findings By highlighting how scientists’ conceptualization of the gene has advanced over time, we aim to help students appreciate the process of discovery that has led to an ever more sophisticated understanding of hereditary information Concept Question A new feature, found as the second question in the Problems and Discussion Questions at the end of each chapter, asks the student to review and comment on common aspects of the Chapter Concepts, listed at the beginning of each chapter This feature places added emphasis on our pedagogic approach of conceptual learning Neurogenetics A major change that is evident in the Table of Contents involves Chapter 24 Previously entitled Behavior Genetics, this chapter has been reworked and redefined to reflect the wealth of information regarding the impact of genetics on the field of neurobiology, linking genetic analysis to brain function and brain disorders Thus, the fully revised Chapter 24 is now entitled Neurogenetics MasteringGenetics This robust online homework and assessment program guides students through complex topics in genetics, using in-depth tutorials that coach students to correct answers with hints and feedback specific to their misconceptions New content for Concepts of Genetics 11e includes a library of Practice Problems that are like end of chapter questions and only appear in MasteringGenetics These problems offer a valuable extension of questions available for assignments These questions include wrong answer feedback to help students learn from their mistakes New and Updated Topics While we have revised each chapter in the text to present the most current findings in genetics, below is a list of some of the most significant new and updated topics present in this edition Ch 1: Introduction to Genetics •  New chapter introduction vignette emphasizing translational medicine A01_KLUG7260_11_GE_FM.indd 29 Ch 3: Mendelian Genetics •  New Understanding Gene Function section: Identifying Mendel’s Gene for Regulating White Flower Color in Peas •  New end-of-chapter problems based on Migaloo, the albino hump-backed whale Ch 7: Sex Determination and Sex Chromosomes •  New coverage on paternal age effects (PAEs) in humans •  New Understanding Gene Function section: Drosophila Sxl Gene Induces Female Development Ch 8: Chromosome Mutations: Variation in Number and Arrangement •  Updated coverage of fragile-X syndrome •  New Understanding Gene Function section: Mouse Models of Down Syndrome Ch 9: Extranuclear Inheritance •  New coverage on mitochondrial swapping and the prevention of mtDNA-based disorders Ch 11: DNA Replication and Recombination •  Updated coverage of DNA Pol III holoenzyme •  Revised figures involving DNA synthesis •  New coverage of the initiation of bacterial DNA synthesis •  New coverage of homologous recombination and gene conversion •  New coverage of replication of telomeric DNA •  New Understanding Gene Function section: Lethal Knockouts of DNA Ligase Genes Ch 12: DNA Organization in Chromosomes •  New coverage of kinetochore structure and function Ch 14: Translation and Proteins •  Revision of all ribosome figures Ch 15: Gene Mutation, DNA Repair, and Transposition •  New data on spontaneous mutation rates in humans •  Reorganization and updates for mutation classification •  Updated coverage of xeroderma pigmentosum and DNA repair mechanisms •  New Understanding Gene Function section: Transposon-Mediated Mutations Reveal Genes Involved in Colorectal Cancer Ch 16: Regulation of Gene Expression in Prokaryotes •  Updated coverage of gene regulation by riboswitches 27/08/15 4:02 PM www.downloadslide.com 30 Preface Ch 17: Regulation of Gene Expression in Eukaryotes •  Expanded coverage of chromatin modifications •  Introduction of Weintraub and Groudine’s experiments involving chromatin structure and transcription regulation •  Updated coverage of promoter and enhancer structures and functions •  Updated coverage of the mechanisms of transcription activation and repression •  Updated section on RNA silencing •  New section: ENCODE Data Are Transforming Our Concepts of Eukaryotic Gene Regulation •  New Understanding Gene Function section: MicroRNAs Regulate Ovulation in Female Mice Ch 18: Developmental Genetics •  New section: Binary Switch Genes and Signaling Pathways, including four new figures •  New Understanding Gene Function section: SingleGene Signaling Mechanism Reveals Secrets to Head Regeneration in Planaria Ch 19: Cancer and Regulation of the Cell Cycle •  New coverage of the progressive nature of colorectal cancers •  Revised and updated coverage of driver and passenger mutations •  Expanded coverage of the role of viruses in human cancers Ch 20: Recombinant DNA Technology •  Expanded coverage and new figure on thirdgeneration DNA sequencing •  New section on gene targeting that includes content and figures on gene knockout animals, conditional knockouts, and transgenic animals Ch 21: Genomics, Bioinformatics, and Proteomics •  Updated coverage of the Human Microbiome Project •  New content introducing exome sequencing •  Updated coverage of personal genome projects •  Revised and expanded coverage of the Encyclopedia of DNA Elements (ENCODE) Project •  New content and figure covering chromatinimmunoprecipitation (ChIP) and ChIP-sequencing (ChIPSeq) •  New Case Study discussing the microbiome as a risk factor for disease Ch 22: Applications and Ethics of Genetic Engineering and Biotechnology •  New section and figure on Synthetic Biology for Bioengineering Applications A01_KLUG7260_11_GE_FM.indd 30 •  New coverage and figure on deducing fetal genome sequences from maternal blood •  Updated coverage of prenatal genetic testing •  Updated coverage of the minimal genome •  New coverage involving genetic analysis by sequencing individual genomes for clinical purposes and single-cell sequencing •  Revised ethics section to include additional discussion on the analysis of whole genome sequences, preconception testing, DNA patents, and destiny predictions •  Major revision of PDQ content and additional new questions •  New Genetics, Technology, and Society essay: Privacy and Anonymity of Genomic Data •  New Case Study on cancer-killing bacteria Ch 23: Quantitative Genetics and Multifactorial Traits •  Updated coverage of quantitative trait loci (QTL) in studying multifactorial phenotypes Ch 24: Neurogenetics •  Conversion of the Behavior Genetics chapter to one entitled Neurogenetics, with emphasis on molecular events in the brain and nervous system related to behavior Includes 10 new figures and new tables •  New Understanding Gene Function section: RbAp48 and a Potential Molecular Mechanism for AgeRelated Memory Loss Ch 25: Population and Evolutionary Genetics •  New coverage on macroevolution and the rate of speciation •  Revision of the discussion of the molecular clock •  Two new sections: The Complex Origins of Our Genome and Our Genome Is a Mosaic Special Topic Chapter 1: Epigenetics •  New section: MicroRNAs and Long Non-Coding RNAs Special Topic Chapter 2: Emerging Roles of RNA •  New chapter on the newly discovered emerging roles of RNA—focuses on the diverse functions of RNAs with an emphasis on noncoding RNA Special Topic Chapter 3: DNA Forensics •  New coverage describing how DNA can be inadvertently transferred to a crime scene, leading to false arrests •  New coverage of DNA phenotyping 27/08/15 4:02 PM www.downloadslide.com P reface 31 Special Topic Chapter 4: Genomics and Personalized Medicine •  New coverage on personal genomics and cancer, including new story of one person’s successful experience using “omics” profiling to select a personalized cancer treatment •  Updated coverage of personalized medicine and disease diagnostics •  Updated coverage of recent studies using “omics” profiles to predict and monitor disease states Special Topic Chapter 5: Genetically Modified Foods •  New chapter on genetically modified foods—the genetic technology behind them, the promises, debates, and controversies Special Topic Chapter 6: Gene Therapy •  New chapter on the modern aspects of gene therapy—provides up-to-date applications of gene therapy in humans To aid students in identifying the conceptual aspects of a major topic, each chapter begins with a section called Chapter Concepts, which identifies the most important ideas about to be presented Each chapter ends with a section called Summary Points, which enumerates the five to ten key points that have been discussed And in the How Do We Know? question that starts each chapter’s problem set, students are asked to connect concepts to experimental findings This question is then followed by a feature new to this edition called Concept Question, which, asks the student to review and comment on common aspects of the Chapter Concepts Collectively, these features help to ensure that students easily become aware of and understand the major conceptual issues as they confront the extensive vocabulary and the many important details of genetics Carefully designed figures also support this approach throughout the book Strengths of This Edition ■ Glossary •  Many definitions refined •  Approximately two dozen new terms Emphasis on Concepts The title of our textbook—Concepts of Genetics—was purposefully chosen, reflecting our fundamental pedagogic approach to teaching and writing about genetics However, the word “concept” is not as easy to define as one might think Most simply put, we consider a concept to be a cognitive unit of meaning—an abstract representation that encompasses a related set of scientifically derived findings and ideas Thus, a concept provides a broad mental image which, for example, might reflect a straightforward snapshot in your mind’s eye of what constitutes a chromosome, a dynamic vision of the detailed processes of replication, transcription, and translation of genetic information, or just an abstract perception of varying modes of inheritance We think that creating such mental imagery is the very best way to teach science, in this case, genetics Details that might be memorized, but soon forgotten, are instead subsumed within a conceptual framework that is easily retained Such a framework may be expanded in content as new information is acquired and may interface with other concepts, providing a useful mechanism to integrate and better understand related processes and ideas An extensive set of concepts may be devised and conveyed to eventually encompass and represent an entire discipline—and this is our goal in this genetics textbook A01_KLUG7260_11_GE_FM.indd 31 ■ Organization—We have continued to attend to the organization of material by arranging chapters within major sections to reflect changing trends in genetics Of particular note is Part IV, which combines the chapter providing foundational coverage of Recombinant DNA Technology with two chapters involving Genomics Pedagogy—As discussed above, one of the major pedagogic goals of this edition is to provide features within each chapter that small groups of students can use either in the classroom or as assignments outside of class Pedagogic research continues to support the value and effectiveness of such active and cooperative learning experiences To this end, there are five features that greatly strengthen this edition ■ Case Study This feature, at the end of each chapter, introduces a short vignette (a “Case”) of an everyday encounter related to genetics, followed by a series of discussion questions Use of the Case Study should prompt students to relate their newly acquired information in genetics to issues that they may encounter away from the course ■ Genetics, Technology, and Society This feature provides a synopsis of a topic related to a current finding in genetics that impacts directly on our current society It now includes a new section called Your Turn, which directs students to related resources of short readings and Web sites to support deeper investigation and discussion of the main topic of each essay ■ Exploring Genomics This feature extends the discussion of selected topics present in the chapter by exploring new findings resulting from genomic studies Students are directed to Web sites that provide the “tools” that research scientists around the world rely on for current genomic information 27/08/15 4:02 PM www.downloadslide.com 32 Preface Whether instructors use these activities as active learning in the classroom or as assigned interactions outside of class, the above features will stimulate the use of current pedagogic approaches to students’ learning The activities help engage students, and the content of each feature ensures that they will become knowledgeable about cutting-edge topics in genetics asks the student to identify and examine the experimental basis underlying important concepts and conclusions that have been presented in the chapter Addressing these questions will aid the student in more fully understanding, rather than memorizing, the end-point of each body of research This feature is an extension of the learning approach in biology first formally descibed by John A Moore in his 1999 book Science as a Way of Knowing—The Foundation of Modern Biology Emphasis on Problem Solving As authors and teachers, we have always recognized the importance of teaching students how to become effective problem solvers Students need guidance and practice if they are to develop strong analytical thinking skills To that end, we present a suite of features in every chapter to optimize opportunities for student growth in the important areas of problem solving and analytical thinking ■ ■ ■ ■ Now Solve This Found several times within the text of each chapter, each entry provides a problem similar to those found at the end of the chapter that is closely related to the current text discussion In each case, a pedagogic hint is provided to offer insight and to aid in solving the problem This feature closely links the text discussion to the problem Insights and Solutions As an aid to the student in learning to solve problems, the Problems and Discussion Questions section of each chapter is preceded by what has become an extremely popular and successful section Insights and Solutions poses problems or questions and provides detailed solutions or analytical insights as answers are provided The questions and their solutions are designed to stress problem solving, quantitative analysis, analytical thinking, and experimental rationale Collectively, these constitute the cornerstone of scientific inquiry and discovery Problems and Discussion Questions Each chapter ends with an extensive collection of Problems and Discussion Questions These include several levels of difficulty, with the most challenging (Extra-Spicy Problems) located at the end of each section Often, Extra-Spicy Problems are derived from the current literature of genetic research, with citations Brief answers to all even-numbered problems are presented in Appendix B How Do We Know? Appearing as the first entry in the Problems and Discussion Questions section, this question A01_KLUG7260_11_GE_FM.indd 32 ■ MasteringGenetics Tutorials in MasteringGenetics help students strengthen their problem-solving skills while exploring challenging activities about key genetics content In addition, end-of-chapter problems are also available for instructors to assign as online homework Students will also be able to access materials in the Study Area that help them assess their understanding and prepare for exams For the Instructor MasteringGenetics— http://www.masteringgenetics.com MasteringGenetics engages and motivates students to learn and allows you to easily assign automatically graded activities Tutorials provide students with personalized coaching and feedback Using the gradebook, you can quickly monitor and display student results MasteringGenetics easily captures data to demonstrate assessment outcomes Resources include: ■ ■ ■ ■ In-depth tutorials that coach students with hints and feedback specific to their misconceptions An item library of thousands of assignable questions including end of chapter problems, reading quizzes, and test bank items You can use publisher-created prebuilt assignments to get started quickly Each question can be easily edited to match the precise language you use A new category of Practice Problems are like end of chapter questions in scope and level of difficulty and are found only in MasteringGenetics The bank of questions extends your options for assigning challenging problems Each problem includes specific wrong answer feedback to help students learn from their mistakes and to guide them toward the correct answer A gradebook that provides you with quick results and easy-to-interpret insights into student performance 27/08/15 4:02 PM www.downloadslide.com P reface 33 TestGen EQ Computerized Testing Software Test questions are available as part of the TestGen EQ Testing Software, a text-specific testing program that is networkable for administering tests It also allows instructors to view and edit questions, export the questions as tests, and print them out in a variety of formats For the Student MasteringGenetics— http://www.masteringgenetics.com Used by over one million science students, the Mastering platform is the most effective and widely used online tutorial, homework, and assessment system for the sciences; it helps students perform better on homework and exams As an instructor-assigned homework system, MasteringGenetics is designed to provide students with a variety of assessment tools to help them understand key topics and concepts and to build problem-solving skills MasteringGenetics tutorials guide students through the toughest topics in genetics with self-paced tutorials that provide individualized coaching with hints and feedback specific to a student’s individual misconceptions Students can also explore the MasteringGenetics Study Area, which includes animations, the eText, Exploring Genomics exercises, and other study aids The interactive eText allows students to highlight text, add study notes, review instructor’s notes, and search throughout the text Acknowledgments Contributors We begin with special acknowledgments to those who have made direct contributions to this text Foremost, we are pleased to thank Dr Darrell Killian of Colorado College for writing the Special Topic chapter on Emerging Roles of RNA We much appreciate this important contribution We also thank Jutta Heller of the University of Washington—Tacoma, Christopher Halweg of North Carolina State University, Pamela Osenkowski of Loyola University—Chicago, and John Osterman of the University of Nebraska—Lincoln for their work on the media program Virginia McDonough of Hope College provided invaluable feedback on our new feature, Modern Approaches to Understanding Gene Function, as well as contributing to the instructor resources along with Cindy Malone of California State University—Northridge We also express special thanks to Harry Nickla, recently retired from Creighton University In his role as author of the Student Handbook and Solutions Manual and the test bank, he has reviewed and edited the problems at the end of each chapter and has written many of the new entries as well He also provided the brief answers to selected problems that appear in Appendix B We are grateful to all of these contributors not only for sharing their genetic expertise, but for their dedication to this project as well as the pleasant interactions they provided A01_KLUG7260_11_GE_FM.indd 33 Proofreaders and Accuracy Checking Reading the manuscript of an 800+ page textbook deserves more thanks than words can offer Our utmost appreciation is extended to Mary Colavito, Santa Monica College; David Kass, Eastern Michigan University; Kirkwood Land, University of the Pacific; Te-Wen Lo, Ithaca College; Pamela Osenkowski, Loyola University—Chicago; John Osterman, University of Nebraska—Lincoln; and Adam Sowalsky, Northeastern University, who provided accuracy checking of many chapters, and to Joanna Dinsmore, who proofread the entire manuscript They confronted this task with patience and diligence, contributing greatly to the quality of this text Reviewers All comprehensive texts are dependent on the valuable input provided by many reviewers While we take full responsibility for any errors in this book, we gratefully acknowledge the help provided by those individuals who reviewed the content and pedagogy of this edition: Soochin Cho, Creighton University Mary Colavito, Santa Monica College Edison Fowlks, Hampton University Yvette Gardner, Clayton State University Theresa Geiman, Loyola University—Maryland Christopher Harendza, Montgomery County Community College Lucinda Jack, University of Maryland David Kass, Eastern Michigan University Kirkwood Land, University of the Pacific Te-Wen Lo, Ithaca College Virginia McDonough, Hope College Amy McMIllan, SUNY Buffalo State Sanghamitra Mohanty, University of Texas—Austin Sudhir Nayak, The College of the New Jersey Pamela Osenkowski, Loyola University—Chicago John Osterman, University of Nebraska—Lincoln Pamela Sandstrom, Unviersity of Nevada—Reno Adam Sowalsky, Northeastern University James D Tucker, Wayne State University Jonathan Visick, North Central College Fang-Sheng Wu, Virginia Commonwealth University Special thanks go to Mike Guidry of LightCone Interactive and Karen Hughes of the University of Tennessee for their original contributions to the media program As these acknowledgments make clear, a text such as this is a collective enterprise All of the above individuals deserve to share in any success this text enjoys We want them to know that our gratitude is equaled only by the extreme dedication evident in their efforts Many, many thanks to them all 27/08/15 4:02 PM www.downloadslide.com 34 Preface Editorial and Production Input At Pearson, we express appreciation and high praise for the editorial guidance of Michael Gillespie, whose ideas and efforts have helped to shape and refine the features of this edition of the text Dusty Friedman, our Project Editor, has worked tirelessly to keep the project on schedule and to maintain our standards of high quality In addition, our editorial team—Deborah Gale, Executive Director of Development, Daniel Ross, Senior Media Producer, and Tania Mlawer, Director of Editorial Content for MasteringGenetics—have provided valuable input into the current edition They have worked creatively to ensure that the pedagogy and design of the book and media package are at the cutting edge of a rapidly changing discipline Sudhir Nayak of The College of New Jersey provided outstanding work for the MasteringGenetics program and his input regarding genomics is much appreciated Lori Newman and Rose Kernan supervised all of the production intricacies with great attention to detail and perseverance Outstand- A01_KLUG7260_11_GE_FM.indd 34 ing copyediting was performed by Betty Pessagno, for which we are most grateful Lauren Harp has professionally and enthusiastically managed the marketing of the text Finally, the beauty and consistent presentation of the art work are the product of Imagineering of Toronto Without the work ethic and dedication of the above individuals, the text would never have come to fruition The publishers would like to thank the following for their contribution to the Global Edition: Contributors Elizabeth R Martin, D.Phil Sreeparna Banerjee, Middle East Technical University A Elif Erson-Bensan, Middle East Technical University Reviewers Juan-Pablo Labrador, Trinity College Dublin Francisco Ramos Morales, University of Seville Shefali Sabharanjak, Ph.D 27/08/15 4:02 PM www.downloadslide.com Newer model organisms in genetics include the roundworm Caenorhabditis elegans, the zebrafish, Danio rerio, and the mustard plant Arabidopsis thaliana Introduction to Genetics Chapter Concepts ■ Genetics in the twenty-first century is built on a rich tradition of discovery and experimentation stretching from the ancient world through the nineteenth century to the present day ■ Transmission genetics is the general process by which traits controlled by genes are transmitted through gametes from generation to generation ■ Mutant strains can be used in genetic crosses to map the location and distance between genes on chromosomes ■ The Watson–Crick model of DNA structure explains how genetic information is stored and expressed This discovery is the foundation of molecular genetics ■ Recombinant DNA technology revolutionized genetics, was the foundation for the Human Genome Project, and has generated new fields that combine genetics with information technology ■ Biotechnology provides genetically modified organisms and their products that are used across a wide range of fields including agriculture, medicine, and industry ■ Model organisms used in genetics research are now utilized in combination with recombinant DNA technology and genomics to study human diseases ■ Genetic technology is developing faster than the policies, laws, and conventions that govern its use I nformation from the Human Genome Project and other areas of genetics is beginning to have far-reaching effects on our daily lives For example, researchers and clinicians are using this information to improve the quality of medical care via translational medicine, a process in which genetic findings are directly “translated” into new and improved methods of diagnosis and treatment An important area of focus is cardiovascular disease, which is the leading cause of death worldwide One of the key risk factors for development of this condition is the presence of elevated blood levels of “bad” cholesterol (low-density lipoprotein cholesterol, or LDL cholesterol) Although statin drugs are effective in lowering the blood levels of LDL cholesterol and reducing the risk of heart disease, up to 50 percent of treated individuals remain at risk, and serious side-effects prevent others from using these drugs To gain a share of the estimated $25 billion market for treatment of elevated LDL levels, major pharmaceutical firms are developing a new generation of more effective cholesterollowering drugs However, bringing a new drug to market is risky Costs can run over $1 billion, and many drugs (up to in 3) fail clinical trials and are withdrawn In the search for a new strategy in drug development, human genetics is playing an increasingly vital role Blood levels of LDL in a population vary over a threefold range, and about 50 percent of this variation is genetic Although many genes are involved, the role of one gene, PCSK9, in controlling LDL levels is an outstanding example of how a genetic approach has been successful in 35 M01_KLUG7260_11_GE_C01.indd 35 14/08/15 2:46 PM www.downloadslide.com 36 In trod uction to Gen etics identifying drug targets and improving the chance that a new drug will be successful The rapid transfer of basic research on PCSK9 to drug development and its use in treating patients is a pioneering example of translational medicine Soon after the PCSK9 gene was identified, mutant forms of this gene were found to be associated with extremely high levels of LDL cholesterol, resulting in a condition called familial hypercholesterolemia (FH) When this work came to the attention of researchers in Texas, they wondered whether other mutations in PCSK9 might have the opposite effect and drastically lower LDL cholesterol levels To test this idea, they turned to data from the Dallas Heart Study, which collected detailed clinical information, including LDL levels and DNA samples, from 3500 individuals DNA sequencing of PSCK9 from participants with extremely low LDL levels identified two mutations that reduced blood levels of LDL by 40 percent Other work showed that carriers of these mutations had an 88 percent lower risk of heart disease Research established that the PCSK9 protein binds to LDL receptors on liver cells, moving the receptors into the cell where they are broken down Carriers of either of the two mutations have much lower PCSK9 protein levels As a result, liver cells in these individuals have many more LDL receptors, which, in turn, remove more LDL from the blood Using this information, pharmaceutical firms developed an antibody-based drug that binds to the PCKS9 protein and prevents its interaction with LDL receptors, which, in turn, lowers LDL cholesterol levels Successful clinical trials show that this drug reduces LDL blood levels up to 70 percent in the test population; if further rounds of testing are successful, the drug will be on the market in the near future Whatever the outcome in the case of PCKS9, it is clear that coupling genetic research with drug development will play a critical and exciting role in speeding the movement of research findings into medical practice This introductory chapter provides an overview of genetics and a survey of the high points in its history and gives a preliminary description of its central principles and emerging developments All the topics discussed in this chapter will be explored in far greater detail elsewhere in the book This text will enable you to achieve a thorough understanding of modern-day genetics and its underlying principles Along the way, enjoy your studies, but take your responsibilities as a novice geneticist very seriously 1.1 Genetics Has a Rich and Interesting History We don’t know when people first recognized the hereditary nature of certain traits, but archaeological evidence (e.g., pictorial representations, preserved bones and skulls, M01_KLUG7260_11_GE_C01.indd 36 and dried seeds) documents the successful domestication of animals and the cultivation of plants thousands of years ago by the artificial selection of genetic variants from wild populations Between 8000 and 1000 b.c., horses, camels, oxen, and wolves were domesticated, and selective breeding of these species soon followed Cultivation of many plants, including maize, wheat, rice, and the date palm, began around 5000 b.c Such evidence documents our ancestors’ successful attempts to manipulate the genetic composition of species During the Golden Age of Greek culture, the writings of the Hippocratic School of Medicine (500–400 b.c.) and of the philosopher and naturalist Aristotle (384–322 b.c.) discussed heredity as it relates to humans The Hippocratic treatise On the Seed argued that active “humors” in various parts of the body served as the bearers of hereditary traits Drawn from various parts of the male body to the semen and passed on to offspring, these humors could be healthy or diseased, with the diseased humors accounting for the appearance of newborns with congenital disorders or deformities It was also believed that these humors could be altered in individuals before they were passed on to offspring, explaining how newborns could “inherit” traits that their parents had “acquired” in response to their environment Aristotle extended Hippocrates’ thinking and proposed that the male semen contained a “vital heat” with the capacity to produce offspring of the same “form” (i.e., basic structure and capacities) as the parent Aristotle believed that this heat cooked and shaped the menstrual blood produced by the female, which was the “physical substance” that gave rise to an offspring The embryo developed not because it already contained the parts of an adult in miniature form (as some Hippocratics had thought) but because of the shaping power of the vital heat Although the ideas of Hippocrates and Aristotle sound primitive and naive today, we should recall that prior to the 1800s neither sperm nor eggs had been observed in mammals 1600–1850: The Dawn of Modern Biology Between about 300 b.c and 1600 a.d., there were few significant new ideas about genetics However, between 1600 and 1850, major strides provided insight into the biological basis of life In the 1600s, William Harvey studied reproduction and development and proposed the theory of epigenesis, which states that an organism develops from the fertilized egg by a succession of developmental events that eventually transform the egg into an adult The theory of epigenesis directly conflicted with the theory of preformation, which stated that the fertilized egg contains a complete miniature adult, called a homunculus (Figure 1–1) Around 1830, Matthias Schleiden and Theodor Schwann proposed the cell theory, stating that all organisms are composed of 14/08/15 2:46 PM www.downloadslide.com 1.2 G e ne tic s Progre s s e d from Me nde l to DN A i n Le s s Than a C en t u ry © 1964 National Library of Medicine F i g u r e –  Depiction of the homunculus, a sperm containing a miniature adult, perfect in proportion and fully formed (Hartsoeker, N Essay de dioptrique Paris, 1694, p 264 National Library of Medicine) basic structural units called cells, which are derived from preexisting cells The idea of spontaneous generation, the creation of living organisms from nonliving components, was disproved by Louis Pasteur later in the century, and living organisms were then considered to be derived from preexisting organisms and to consist of cells In the mid-1800s the revolutionary work of Charles Darwin and Gregor Mendel set the stage for the rapid development of genetics in the twentieth and twenty-first centuries Charles Darwin and Evolution With this background, we turn to a brief discussion of the work of Charles Darwin, who published The Origin of Species, in 1859, describing his ideas about evolution Darwin’s geological, geographical, and biological observations convinced him that existing species arose by descent with modification from ancestral species Greatly influenced by his voyage on the HMS Beagle (1831–1836), Darwin’s thinking led him to formulate the theory of natural selection, which presented an explanation of the mechanism of evolutionary change Formulated and proposed independently by Alfred Russel Wallace, natural selection is based on the observation that populations tend to contain more offspring than the environment can support, leading to a struggle for survival among individuals Those individuals with heritable traits that allow them to adapt to their M01_KLUG7260_11_GE_C01.indd 37 37 environment are better able to survive and reproduce than those with less adaptive traits Over a long period of time, advantageous variations, even very slight ones, will accumulate If a population carrying these inherited variations becomes reproductively isolated, a new species may result Darwin, however, lacked an understanding of the genetic basis of variation and inheritance, a gap that left his theory open to reasonable criticism well into the twentieth century Shortly after Darwin published his book, Gregor Johann Mendel published a paper in 1866 showing how traits were passed from generation to generation in pea plants and offering a general model of how traits are inherited His research was little known until it was partially duplicated and brought to light by Carl Correns, Hugo de Vries, and Erich Tschermak around 1900 By the early part of the twentieth century, it became clear that heredity and development were dependent on genetic information residing in genes contained in chromosomes, which were then contributed to each individual by gametes—the so-called chromosomal theory of inheritance The gap in Darwin’s theory was closed, and Mendel’s research has continued to serve as the foundation of genetics 1.2 Genetics Progressed from Mendel to DNA in Less Than a Century Because genetic processes are fundamental to life itself, the science of genetics unifies biology and serves as its core The starting point for this branch of science was a monastery garden in central Europe in the late 1850s Mendel’s Work on Transmission of Traits Gregor Mendel, an Augustinian monk, conducted a decadelong series of experiments using pea plants He applied quantitative data analysis to his results and showed that traits are passed from parents to offspring in predictable ways He further concluded that each trait in the plant is controlled by a pair of factors (which we now call genes) and that during gamete formation (the formation of egg cells and sperm), members of a gene pair separate from each other His work was published in 1866 but was largely unknown until it was cited in papers published by others around 1900 Once confirmed, Mendel’s findings became recognized as explaining the transmission of traits in pea plants and all other higher organisms His work forms the foundation for genetics, which is defined as the branch of biology concerned with the study of heredity and variation Mendelian genetics will be discussed later in the text (see Chapters and 4) 14/08/15 2:46 PM www.downloadslide.com 38 In trod ucti on to Gen et ics F i g u r e –   A colorized image of human chromosomes that have duplicated in preparation for cell division, as visualized under the scanning electron microscope The Chromosome Theory of Inheritance: Uniting Mendel and Meiosis Mendel did his experiments before the structure and role of chromosomes were known About 20 years after his work was published, advances in microscopy allowed researchers to identify chromosomes (Figure 1–2) and establish that, in most eukaryotes, members of each species have a characteristic number of chromosomes called the diploid number (2n) in most of their cells For example, humans have a diploid number of 46 (Figure 1–3) Chromosomes in diploid cells exist in pairs, called homologous chromosomes Researchers in the last decades of the nineteenth century also described chromosome behavior during two forms of cell division, mitosis and meiosis In mitosis (Figure 1–4), chromosomes are copied and distributed so that each daughter cell receives a diploid set of chromosomes identical to those in the parental cell Meiosis is associated with gamete formation Cells produced by meiosis receive only one chromosome from each chromosome pair, and the resulting number of chromosomes is called the haploid (n) number This reduction in chromosome number is essential if the offspring arising from the fusion of egg and sperm are to maintain the constant number of chromosomes characteristic of their parents and other members of their species Early in the twentieth century, Walter Sutton and Theodor Boveri independently noted that the behavior of chromosomes during meiosis is identical to the behavior of genes during gamete formation described by Mendel For example, genes and chromosomes exist in pairs, and members of a gene pair and members of a chromosome pair separate from each other during gamete formation Based on these parallels, Sutton and Boveri each proposed that genes are carried on chromosomes (Figure 1–5) They independently formulated the chromosome theory of inheritance, which states that inherited traits are controlled by genes residing on chromosomes M01_KLUG7260_11_GE_C01.indd 38 Figur e 1–3   A colorized image of the human male chromosome set Arranged in this way, the set is called a karyotype faithfully transmitted through gametes, maintaining genetic continuity from generation to generation Genetic Variation About the same time that the chromosome theory of inheritance was proposed, scientists began studying the inheritance of traits in the fruit fly, Drosophila melanogaster Early Figur e 1–4   A late stage in mitosis after the chromosomes (stained blue) have separated 14/08/15 2:46 PM www.downloadslide.com 1.3 Di s c ove ry of the Dou ble He li x Lau nch e d the Er a of M ole c u la r G en eti cs 39 I scute bristles, sc white eyes, w ruby eyes, rb crossveinless wings, cv singed bristles, sn lozenge eyes, lz vermilion eyes, v sable body, s scalloped wings, sd Bar eyes, B carnation eyes, car little fly, lf F i g u r e –   A drawing of chromosome I (the X chromosome, one of the sex-determining chromosomes) of D melanogaster, showing the location of several genes Chromosomes can contain hundreds of genes in this work, a white-eyed fly (Figure 1–6) was discovered among normal (wild-type) red-eyed flies This variation was produced by a mutation in one of the genes controlling eye color Mutations are defined as any heritable change in the DNA sequence and are the source of all genetic variation The white-eye variant discovered in Drosophila is an allele of a gene controlling eye color Alleles are defined as alternative forms of a gene Different alleles may produce differences in the observable features, or phenotype, of an organism The set of alleles for a given trait carried by an organism is called the genotype Using mutant genes as markers, geneticists can map the location of genes on chromosomes (Figure 1–5) The Search for the Chemical Nature of Genes: DNA or Protein? Work on white-eyed Drosophila showed that the mutant trait could be traced to a single chromosome, confirming the idea that genes are carried on chromosomes Once this relationship was established, investigators turned their attention to identifying which chemical component of chromosomes M01_KLUG7260_11_GE_C01.indd 39 Figur e 1–6  The white-eyed mutation in D melanogaster (top) and the normal red eye color (bottom) carries genetic information By the 1920s, scientists knew that proteins and DNA were the major chemical components of chromosomes There are a large number of different proteins, and because of their universal distribution in the nucleus and cytoplasm, many researchers thought proteins were the carriers of genetic information In 1944, Oswald Avery, Colin MacLeod, and Maclyn McCarty, researchers at the Rockefeller Institute in New York, published experiments showing that DNA was the carrier of genetic information in bacteria This evidence, though clear-cut, failed to convince many influential scientists Additional evidence for the role of DNA as a carrier of genetic information came from other researchers who worked with viruses This evidence that DNA carries genetic information, along with other research over the next few years, provided solid proof that DNA, not protein, is the genetic material, setting the stage for work to establish the structure of DNA 1.3 Discovery of the Double Helix Launched the Era of Molecular Genetics Once it was accepted that DNA carries genetic information, efforts were focused on deciphering the structure of the DNA molecule and the mechanism by which information stored in it produces a phenotype 14/08/15 2:46 PM www.downloadslide.com 40 In trod uction to Gen etics P P P P A T C G G C T A Sugar P (deoxyribose) P P Nucleotide Phosphate P Complementary base pair (thymine-adenine) F i g u r e –  Summary of the structure of DNA, illustrating the arrangement of the double helix (on the left) and the chemical components making up each strand (on the right) The dotted lines on the right represent weak chemical bonds, called hydrogen bonds, which hold together the two strands of the DNA helix The Structure of DNA and RNA One of the great discoveries of the twentieth century was made in 1953 by James Watson and Francis Crick, who described the structure of DNA DNA is a long, ladderlike macromolecule that twists to form a double helix (Figure 1–7) Each linear strand of the helix is made up of subunits called nucleotides In DNA, there are four different nucleotides, each of which contains a nitrogenous base, abbreviated A (adenine), G (guanine), T (thymine), or C (cytosine) These four bases, in various sequence combinations, ultimately encode genetic information The two strands of DNA are exact complements of one another, so that the rungs of the ladder in the double helix always consist of A5T and G5C base pairs Along with Maurice Wilkins, Watson and Crick were awarded a Nobel Prize in 1962 for their work on the structure of DNA We will discuss the structure of DNA later in the text (see Chapter 9) Another nucleic acid, RNA, is chemically similar to DNA but contains a different sugar (ribose rather than deoxyribose) in its nucleotides and contains the nitrogenous base uracil in place of thymine RNA, however, is generally a single-stranded molecule Gene Expression: From DNA to Phenotype The genetic information encoded in the order of nucleotides in DNA is expressed in a series of steps that results in the formation of a functional gene product In the majority of cases, this product is a protein In eukaryotic cells, the process leading to protein production begins in the nucleus M01_KLUG7260_11_GE_C01.indd 40 with transcription, in which the nucleotide sequence in one strand of DNA is used to construct a complementary RNA sequence (top part of Figure 1–8) Once an RNA molecule is produced, it moves to the cytoplasm, where the RNA—called messenger RNA, or mRNA for short— binds to a ribosome The synthesis of proteins under the direction of mRNA is called translation (center part of Figure 1–8) The information encoded in mRNA (called the genetic code) consists of a linear series of nucleotide triplets Each triplet, called a codon, is complementary to the information stored in DNA and specifies the insertion of a specific amino acid into a protein Proteins (lower part of Figure 1–8) are polymers made up of amino acid monomers There are 20 different amino acids commonly found in proteins Protein assembly is accomplished with the aid of adapter molecules called transfer RNA (tRNA) Within the ribosome, tRNAs recognize the information encoded in the mRNA codons and carry the proper amino acids for construction of the protein during translation We now know that gene expression can be more complex than outlined here Some of these complexities will be discussed later in the text (see Chapters 14, 17, and Special Topic Chapter 1—Epigenetics) Gene DNA 3’ 5’ TA C C A C A A C T C G DNA template strand Transcription mRNA 5’ 3’ AUGGUGUUGAGC Triplet code words Translation on ribosomes Met Val Leu Ser Protein Amino acids Figur e 1–8   Gene expression consists of transcription of DNA into mRNA (top) and the translation (center) of mRNA (with the help of a ribosome) into a protein (bottom) 14/08/15 2:46 PM www.downloadslide.com 1.3 Di s c ove ry of the Dou ble He li x Lau nch e d the Er a of M ole c u la r G en eti cs Proteins and Biological Function In most cases, proteins are the end products of gene expression The diversity of proteins and the biological functions they perform—the diversity of life itself—arises from the fact that proteins are made from combinations of 20 different amino acids Consider that a protein chain containing 100 amino acids can have at each position any one of 20 amino acids; the number of possible different 100 amino acid proteins, each with a unique sequence, is therefore equal to 20100 Obviously, proteins are molecules with the potential for enormous structural diversity and serve as the mainstay of biological systems Enzymes form the largest category of proteins These molecules serve as biological catalysts, lowering the energy of activation in reactions and allowing cellular metabolism to proceed at body temperature Proteins other than enzymes are critical components of cells and organisms These include hemoglobin, the oxygenbinding molecule in red blood cells; insulin, a pancreatic hormone; collagen, a connective tissue molecule; and actin and myosin, the contractile muscle proteins A protein’s shape and chemical behavior are determined by its linear sequence of amino acids, which in turn are dictated by the stored information in the DNA of a gene that is transferred to RNA, which then directs the protein’s synthesis Linking Genotype to Phenotype: Sickle-Cell Anemia Once a protein is made, its biochemical or structural properties play a role in producing a phenotype When mutation alters a gene, it may modify or even eliminate the encoded protein’s usual function and cause an altered phenotype To trace this chain of events, we will examine sickle-cell anemia, a human genetic disorder Sickle-cell anemia is caused by a mutant form of hemoglobin, the protein that transports oxygen from the lungs to cells in the body Hemoglobin is a composite molecule made up of two different proteins, α-globin and β-globin, each encoded by a different gene In sickle-cell anemia, a mutation in the gene encoding β-globin causes an amino acid substitution in of the 146 amino acids in the protein Figure 1–9 shows the DNA sequence, the corresponding mRNA codons, and the amino acids occupying positions 4–7 for the normal and mutant forms of β-globin Notice that the mutation in sickle-cell anemia consists of a change in one DNA nucleotide, which leads to a change in codon in mRNA from GAG to GUG, which in turn changes amino acid number in β-globin from glutamic acid to valine The other 145 amino acids in the protein are not changed by this mutation M01_KLUG7260_11_GE_C01.indd 41 41 NORMAL 6-GLOBIN DNA mRNA Amino acid MUTANT 6-GLOBIN DNA mRNA Amino acid TGA ACU Thr GGA CCU Pro CTC GAG Glu CTC GAG Glu TGA ACU Thr GGA CCU Pro CAC GUG Val CTC GAG Glu 7 Figur e 1–9   A single-nucleotide change in the DNA encoding β-globin (CTCSCAC) leads to an altered mRNA codon (GAGSGUG) and the insertion of a different amino acid (GluSVal), producing the altered version of the β-globin protein that is responsible for sickle-cell anemia Individuals with two mutant copies of the β-globin gene have sickle-cell anemia Their mutant β-globin proteins cause hemoglobin molecules in red blood cells to polymerize when the blood’s oxygen concentration is low, forming long chains of hemoglobin that distort the shape of red blood cells (Figure 1–10) The deformed cells are fragile and break easily, reducing the number of red blood cells in circulation (anemia is an insufficiency of red blood cells) Sickle-shaped blood cells block blood flow in capillaries and small blood vessels, causing severe pain and damage to the heart, brain, muscles, and kidneys All the symptoms of this disorder are caused by a change in a single nucleotide in a gene that changes one amino acid out of 146 in the β-globin molecule, demonstrating the close relationship between genotype and phenotype Figur e 1–10  Normal red blood cells (round) and sickled red blood cells The sickled cells block capillaries and small blood vessels 14/08/15 2:46 PM www.downloadslide.com 42 In trod ucti on to Gen et ics 1.4 Development of Recombinant DNA Technology Began the Era of DNA Cloning The era of recombinant DNA began in the early 1970s, when researchers discovered that restriction enzymes, used by bacteria to cut the DNA of invading viruses, could be used to cut any organism’s DNA at specific nucleotide sequences, producing a reproducible set of fragments Soon after, researchers discovered ways to insert the DNA fragments produced by the action of restriction enzymes into carrier DNA molecules called vectors to form recombinant DNA molecules When transferred into bacterial cells, thousands of copies, or clones, of the combined vector and DNA fragments are produced during bacterial reproduction Large amounts of cloned DNA fragments can be isolated from these bacterial host cells These DNA fragments can be used to isolate genes, to study their organization and expression, and to study their nucleotide sequence and evolution Collections of clones that represent an organism’s genome, defined as the complete haploid DNA content of a specific organism, are called genomic libraries Genomic libraries are now available for hundreds of species Recombinant DNA technology has not only accelerated the pace of research but also given rise to the biotechnology industry, which has grown to become a major contributor to the U.S economy 1.5 The Impact of Biotechnology Is Continually Expanding The use of recombinant DNA technology and other molecular techniques to make products is called biotechnology In the United States, biotechnology has quietly revolutionized many aspects of everyday life; products made by biotechnology are now found in the supermarket, in health care, in agriculture, and in the court system A later chapter (see Chapter 19) contains a detailed discussion of biotechnology, but for now, let’s look at some everyday examples of biotechnology’s impact Plants, Animals, and the Food Supply The use of recombinant DNA technology to genetically modify crop plants has revolutionized agriculture Genes for traits including resistance to herbicides, insects, and genes for nutritional enhancement have been introduced into crop plants The transfer of heritable traits M01_KLUG7260_11_GE_C01.indd 42 Figur e 1–11  Dolly, a Finn Dorset sheep cloned from the genetic material of an adult mammary cell, shown next to her first-born lamb, Bonnie across species using recombinant DNA technology creates transgenic organisms Herbicide-resistant corn and soybeans were first planted in the mid-1990s, and transgenic strains now represent about 88 percent of the U.S corn crop and 93 percent of the U.S soybean crop It is estimated that more than 70 percent of the processed food in the United States contains ingredients from transgenic crops We will discuss the most recent findings involving genetically modified organisms later in the text (Special Topic Chapter 5—Genetically Modified Organisms) New methods of cloning livestock such as sheep and cattle have also changed the way we use these animals In 1996, Dolly the sheep (Figure 1–11) was cloned by nuclear transfer, a method in which the nucleus of an adult cell is transferred into an egg that has had its nucleus removed This method makes it possible to produce dozens or hundreds of genetically identical offspring with desirable traits and has many applications in agriculture, sports, and medicine Biotechnology has also changed the way human proteins for medical use are produced Through use of gene transfer, transgenic animals now synthesize these therapeutic proteins In 2009, an anticlotting protein derived from the milk of transgenic goats was approved by the U.S Food and Drug Administration for use in the United States Other human proteins from transgenic animals are now being used in clinical trials to treat several diseases The biotechnology revolution will continue to expand as new methods are developed to make an increasing array of products 14/08/15 2:46 PM www.downloadslide.com 1.6 Genomic s , Prote omic s , and Bioinform atic s A re Ne w a nd Expa n din g Fi el d s 43 DNA test currently available Adrenoleukodystrophy (ALD) Fatal nerve disease Azoospermia Absence of sperm in semen Muscular Dystrophy Progressive deterioration of the muscles Gaucher Disease A chronic enzyme deficiency occurring frequently among Ashkenazi Jews Hemophilia A Clotting deficiency Ehlers–Danlos Syndrome Connective tissue disease Glucose-Galactose Malabsorption Syndrome Potentially fatal digestive disorder Retinitis Pigmentosa Progressive degeneration of the retina Amyotrophic Lateral Sclerosis (ALS) Late-onset lethal degenerative nerve disease Huntington Disease Lethal, late-onset, nerve degenerative disease ADA Immune Deficiency First hereditary condition treated by gene therapy Familial Adenomatous Polyposis (FAP) Intestinal polyps leading to colon cancer Familial Hypercholesterolemia Extremely high cholesterol Myotonic Dystrophy Form of adult muscular dystrophy 21 20 19 Amyloidosis Accumulation in the tissues of an insoluble fibrillar protein 18 17 22 X Y Human chromosome number 16 Neurofibromatosis (NF1) Benign tumors of nerve tissue below the skin Hemochromatosis Abnormally high absorption of iron from the diet 15 14 13 12 11 10 Breast Cancer 5% of all cases Spinocerebellar Ataxia Destroys nerves in the brain and spinal cord, resulting in loss of muscle control Cystic Fibrosis Mucus in lungs, interfering with breathing Werner Syndrome Premature aging Melanoma Tumors originating in the skin Polycystic Kidney Disease Cysts resulting in enlarged kidneys and renal failure Multiple Endocrine Neoplasia, Type Tumors in endocrine gland and other tissues Tay–Sachs Disease Fatal hereditary disorder involving lipid metabolism often occurring in Ashkenazi Jews Alzheimer Disease Degenerative brain disorder marked by premature senility Retinoblastoma Childhood tumor of the eye Sickle-Cell Anemia Chronic inherited anemia, in which red blood cells sickle, clogging arterioles and capillaries Phenylketonuria (PKU) An inborn error of metabolism; if untreated, results in mental retardation F i g u re – 12  The human chromosome set, showing the location of some genes whose mutant forms cause hereditary diseases Conditions that can be diagnosed using genetic testing are indicated by a red dot Biotechnology in Genetics and Medicine More than 10 million children or adults in the United States suffer from some form of genetic disorder, and every childbearing couple faces an approximately percent risk of having a child with a genetic anomaly The molecular basis for hundreds of genetic disorders is now known, and many of these genes have been mapped, isolated, and cloned (Figure 1–12) Biotechnology-derived genetic testing is now available to perform prenatal diagnosis of heritable disorders and to test parents for their status as “carriers” of more than 100 inherited disorders Newer methods now under development offer the possibility of scanning an entire genome to establish an individual’s risk of developing a genetic disorder or having an affected child The use of genetic testing and related technologies raises ethical concerns that have yet to be resolved M01_KLUG7260_11_GE_C01.indd 43 1.6 Genomics, Proteomics, and Bioinformatics Are New and Expanding Fields The use of recombinant DNA technology to create genomic libraries prompted scientists to consider sequencing all the clones in a library to derive the nucleotide sequence of an organism’s genome This sequence information would be used to identify each gene in the genome and establish its function One such project, the Human Genome Project, began in 1990 as an international effort to sequence the human genome By 2003, the publicly funded Human Genome Project and a private, industry-funded genome project completed sequencing of the gene-containing portion of the genome 14/08/15 2:46 PM www.downloadslide.com 44 In trod ucti on to Gen et ics As more genome sequences were acquired, several new biological disciplines arose One, called genomics (the study of genomes), studies the structure, function, and evolution of genes and genomes A second field, proteomics, identifies the set of proteins present in a cell under a given set of conditions, and studies their functions and interactions To store, retrieve, and analyze the massive amount of data generated by genomics and proteomics, a specialized subfield of information technology called bioinformatics was created to develop hardware and software for processing nucleotide and protein data Geneticists and other biologists now use information in databases containing nucleic acid sequences, protein sequences, and gene-interaction networks to answer experimental questions in a matter of minutes instead of months and years A feature called “Exploring Genomics,” located at the end of many of the chapters in this textbook, gives you the opportunity to explore these databases for yourself while completing an interactive genetics exercise gene knockout render targeted genes nonfunctional in a model organism or in cultured cells, allowing scientists to investigate the fundamental question of “what happens if this gene is disrupted?” After making a knockout organism, scientists look for both apparent phenotype changes, as well as those at the cellular and molecular level The ultimate goal is to determine the function of the gene In “Modern Approaches to Understanding Gene Function” we will highlight experimental examples of how gene function has been revealed through modern applications of molecular techniques involving reverse genetics You will learn about gene knockout, transgenic animals, transposonmediated mutagenesis, gene overexpression, and RNA interference-based methods for interrupting genes, among other approaches Our hope is to bring you to the “cutting edge” of genetic studies Modern Approaches to Understanding Gene Function of Model Organisms New to this edition of Concepts of Genetics is “Modern Approaches to Understanding Gene Function.” This feature appears in eight chapters and its purpose is to introduce you to examples of current experimental approaches that geneticists use to study gene function Its location in selected chapters links experimental examples of understanding gene function to the concepts that have just been presented Historically, an approach referred to as classical or forward genetics was essential for studying and understanding gene function In this approach geneticists relied on the use of naturally occurring mutations or they intentionally induced mutations (using chemicals, X-rays or UV light as examples) to cause altered phenotypes in model organisms, and then worked through the lab-intensive and time-consuming process of identifying the genes that caused these new phenotypes Such characterization often led to the identification of the gene or genes of interest, and once the technology advanced, the gene sequence could be determined Classical genetics approaches are still used, but as whole genome sequencing has become routine, molecular approaches to understanding gene function have changed considerably in genetic research These modern approaches are what we will highlight in this feature For the past two decades or so, geneticists have relied on the use of molecular techniques incorporating an approach referred to as reverse genetics In reverse genetics, the DNA sequence for a particular gene of interest is known, but the role and function of the gene are typically not well understood For example, molecular biology techniques such as M01_KLUG7260_11_GE_C01.indd 44 1.7 Genetic Studies Rely on the Use After the rediscovery of Mendel’s work in 1900, research using a wide range of organisms confirmed that the principles of inheritance he described were of universal significance among plants and animals Geneticists gradually came to focus attention on a small number of organisms, including the fruit fly (Drosophila melanogaster) and the mouse (Mus musculus) (Figure 1–13) This trend developed for two main reasons: first, it was clear that genetic mechanisms were the same in most organisms, and second, these organisms had characteristics that made them especially suitable for genetic research They were easy to grow, had relatively short life cycles, produced many offspring, and their genetic analysis was fairly straightforward Over time, researchers (a) (b) Figur e 1–13  The first generation of model organisms in genetic analysis included (a) the mouse, Mus musculus and (b) the fruit fly, Drosophila melanogaster 14/08/15 2:46 PM www.downloadslide.com 1.7 G e ne tic S tu die s R e ly on t he Us e of M ode l Organ i s m s 45 Ta ble 1.1   Model Organisms Used to Study Some Human Diseases (a) (b) F i g u r e – 14  Microbes that have become model organisms for genetic studies include (a) the yeast Saccharomyces cerevisiae and (b) the bacterium Escherichia coli created a large catalog of mutant strains for these species, and the mutations were carefully studied, characterized, and mapped Because of their well-characterized genetics, these species became model organisms, defined as organisms used for the study of basic biological processes In later chapters, we will see how discoveries in model organisms are shedding light on many aspects of biology, including aging, cancer, the immune system, and behavior The Modern Set of Genetic Model Organisms Gradually, geneticists added other species to their collection of model organisms: viruses (such as the T phages and lambda phage) and microorganisms (the bacterium Escherichia coli and the yeast Saccharomyces cerevisiae) (Figure 1–14) More recently, additional species have been developed as model organisms, three of which are shown in the chapter opening photograph Each species was chosen to allow study of some aspect of embryonic development The nematode Caenorhabditis elegans was chosen as a model system to study the development and function of the nervous system because its nervous system contains only a few hundred cells and the developmental fate of these and all other cells in the body has been mapped out Arabidopsis thaliana, a small plant with a short life cycle, has become a model organism for the study of many aspects of plant biology The zebrafish, Danio rerio, is used to study vertebrate development: it is small, it reproduces rapidly, and its egg, embryo, and larvae are all transparent Model Organisms and Human Diseases The development of recombinant DNA technology and the results of genome sequencing have confirmed that all life has a common origin Because of this, genes with similar functions in different organisms tend to be similar or identical in structure and nucleotide sequence Much of what M01_KLUG7260_11_GE_C01.indd 45 Organism Human Diseases E coli Colon cancer and other cancers S cerevisiae Cancer, Werner syndrome D melanogaster Disorders of the nervous system, cancer C elegans Diabetes D rerio Cardiovascular disease M musculus Lesch–Nyhan disease, cystic fibrosis, fragile-X syndrome, and many other diseases scientists learn by studying the genetics of model organisms can therefore be applied to humans as the basis for understanding and treating human diseases In addition, the ability to create transgenic organisms by transferring genes between species has enabled scientists to develop models of human diseases in organisms ranging from bacteria to fungi, plants, and animals (Table 1.1) The idea of studying a human disease such as colon cancer by using E coli may strike you as strange, but the basic steps of DNA repair (a process that is defective in some forms of colon cancer) are the same in both organisms, and a gene involved (mutL in E coli and MLH1 in humans) is found in both organisms More importantly, E coli has the advantage of being easier to grow (the cells divide every 20 minutes), and researchers can easily create and study new mutations in the bacterial mutL gene in order to figure out how it works This knowledge may eventually lead to the development of drugs and other therapies to treat colon cancer in humans The fruit fly, Drosophila melanogaster, is also being used to study a number of human diseases Mutant genes have been identified in D melanogaster that produce phenotypes with structural abnormalities of the nervous system and adult-onset degeneration of the nervous system The information from genome-sequencing projects indicates that almost all these genes have human counterparts For example, genes involved in a complex human disease of the retina called retinitis pigmentosa are identical to Drosophila genes involved in retinal degeneration Study of these mutations in Drosophila is helping to dissect this complex disease and identify the function of the genes involved Another approach to studying diseases of the human nervous system is to transfer mutant human disease genes into Drosophila using recombinant DNA technology The transgenic flies are then used for studying the mutant human genes themselves, other genes that affect the expression of the human disease genes, and the effects of therapeutic drugs on the action of those genes—all studies that are difficult or impossible to perform in humans This gene transfer 14/08/15 2:46 PM www.downloadslide.com 46 In trod uction to Gen etics approach is being used to study almost a dozen human neurodegenerative disorders, including Huntington disease, Machado–Joseph disease, myotonic dystrophy, and Alzheimer disease Throughout the following chapters, you will encounter these model organisms again and again Remember each time you meet them that they not only have a rich history in basic genetics research but are also at the forefront in the study of human genetic disorders and infectious diseases As discussed in the next section, however, we have yet to reach a consensus on how and when some of this technology will be accepted as safe and ethically acceptable 1.8 We Live in the Age of Genetics Mendel described his decade-long project on inheritance in pea plants in an 1865 paper presented at a meeting of the Natural History Society of Brünn in Moravia Less than 100 years later, the 1962 Nobel Prize was awarded to James Watson, Francis Crick, and Maurice Wilkins for their work on the structure of DNA This time span encompassed the years leading up to the acceptance of Mendel’s work, the discovery that genes are on chromosomes, the experiments that proved DNA encodes genetic information, and the elucidation of the molecular basis for DNA replication The rapid development of genetics from Mendel’s monastery garden to the Human Genome Project and beyond is summarized in a timeline in Figure 1–15 The Nobel Prize and Genetics No other scientific discipline has experienced the explosion of information and the level of excitement generated by the discoveries in genetics This impact is especially apparent in the list of Nobel Prizes related to genetics, beginning with those awarded in the early and mid-twentieth century and continuing into the present (see inside front cover) Nobel Prizes in Medicine or Physiology and Chemistry have been consistently awarded for work in genetics and related fields The first Nobel Prize awarded for such work was given to Thomas Morgan in 1933 for his research on the chromosome theory of inheritance That award was followed by many others, including prizes for the discovery of genetic recombination, the relationship between genes and proteins, the structure of DNA, and the genetic code In this century, geneticists continue to be recognized for their impact on biology in the current millennium, including Nobel Prizes awarded in 2002, 2006, 2007, and 2009 In 2010, the prize in Physiology or Medicine was given to Robert Edwards for the development of in vitro fertilization, and the 2012 prize was awarded to John Gurdon and Shinya Yamanaka for their work showing that mature cells can be reprogrammed to direct embryonic development and to form stem cells Genetics and Society Just as there has never been a more exciting time to study genetics, the impact of this discipline on society has never been more profound Genetics and its applications in biotechnology are developing much faster than the social conventions, public policies, and laws required to regulate their use As a society, we are grappling with a host of sensitive genetics-related issues, including concerns about prenatal testing, genetic discrimination, ownership of genes, access to and safety of gene therapy, and genetic privacy By the time you finish this course, you will have seen more than enough evidence to convince yourself that the present is the Age of Genetics, and you will understand the need to think about and become a participant in the dialogue concerning genetic science and its use DNA shown to carry genetic information Watson–Crick model of DNA Mendel’s work published Chromosome theory of inheritance proposed Transmission genetics evolved Recombinant DNA technology developed DNA cloning begins Application of genomics begins 1860s 1870s 1880s 1890s 1900s 1910s 1920s 1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s Mendel’s work rediscovered, correlated with chromosome behavior in meiosis Era of molecular genetics Gene expression, regulation understood Genomics begins Human Genome Project initiated F i g u r e – 15   A timeline showing the development of genetics from Gregor Mendel’s work on pea plants to the current era of genomics and its many applications in research, medicine, and society Having a sense of the history of discovery in genetics should provide you with a useful framework as you proceed through this textbook M01_KLUG7260_11_GE_C01.indd 46 14/08/15 2:46 PM www.downloadslide.com E xp loring G en o mi cs 47 G e n e t i c s , T e c h n o l o g y, a n d S o c i e t y O The Scientific and Ethical Implications of Modern Genetics ne of the special features of this text is the series of essays called Genetics, Technology, and Society that you will find at the conclusion of many chapters These essays explore genetics-related topics that have an impact on the lives of each of us and on society in general Today, genetics touches all aspects of life, bringing rapid changes in medicine, agriculture, law, biotechnology, and the pharmaceutical industry Physicians use hundreds of genetic tests to diagnose and predict the course of disease and to detect genetic defects in utero Scientists employ DNA-based methods to trace the path of evolution taken by many species, including our own Farmers grow disease-resistant and drought-resistant crops, and raise more productive farm animals, created by gene transfer techniques Law enforcement agencies apply DNA profiling methods to paternity, rape, and murder investigations The biotechnology industry itself generates over 700,000 jobs and $50 billion in revenue each year and doubles in size every decade Along with these rapidly changing gene-based technologies comes a challenging array of ethical dilemmas Who owns and controls genetic information? Are gene-enhanced agricultural plants and animals safe for humans and the environment? How can we ensure that genomic technologies will be available to all and not just to the wealthy? What are the likely social consequences of the new reproductive technologies? It is a time when everyone needs to understand genetics in order to make complex personal and societal decisions Each Genetics, Technology, and Society essay is presented in an interactive format In the Your Turn section at the end of each essay, you will find several thoughtprovoking questions along with resources to help you explore each question These questions are designed to act as entry points for individual investigations and as topics to explore in a classroom or group learning setting We hope that you will find the Genetics, Technology, and Society essays interesting, challenging, and an effective way to begin your lifelong studies in modern genetics Good reading! Exploring Genomics G Internet Resources for Learning about Genomics, Bioinformatics, and Proteomics enomics is one of the most rapidly changing disciplines of genetics As new information in this field accumulates at an astounding rate, keeping up with current developments in genomics, proteomics, bioinformatics, and other examples of the “omics” era of modern genetics is a challenging task indeed As a result, geneticists, molecular biologists, and other scientists rely on online databases to share and compare new information The purpose of the “Exploring Genomics” feature, which appears at the end of many chapters, is to introduce Visit the Study Area: Exploring Genomics you to a range of Internet databases that scientists around the world depend on for sharing, analyzing, organizing, comparing, and storing data from studies in genomics, proteomics, and related fields We will explore this incredible pool of new information—comprising some of the best publicly available resources in the world—and show you how to use bioinformatics approaches to analyze the sequence and structural data that are found there Each set of Exploring Genomics exercises will provide a basic introduction to one or more especially relevant or useful databases or programs and then guide you through exercises that use the databases to expand on or reinforce important concepts discussed in the chapter The exercises are designed to help you learn to navigate the databases, but your explorations need not be limited to these experiences Part of the fun of learning about genomics is exploring these outstanding databases on your own, so that you can get the latest information on any topic that interests you Enjoy your explorations! In this chapter, we discussed the importance of model organisms to both classic and modern experimental approaches (continued) M01_KLUG7260_11_GE_C01.indd 47 14/08/15 2:46 PM www.downloadslide.com 48 In trod ucti on to Gen et ics Exploring Genomics­—continued in genetics In our first set of Exploring Genomics exercises, we introduce you to a number of Internet sites that are excellent resources for finding up-to-date information on a wide range of completed and ongoing genomics projects involving model organisms Exercise I – Genome News Network Since 1995, when scientists unveiled the genome for Haemophilus influenzae, making this bacterium the first organism to have its genome sequenced, the sequences for more than 500 organisms have been completed Genome News Network is a site that provides access to basic information about recently completed genome sequences Visit the Genome News Network at www.genomenewsnetwork.org Click on the “Quick Guide to Sequenced Genomes” link Scroll down the page; click on the appropriate links to find information about the genomes for Anopheles gambiae, Lactococcus lactis, and Pan troglodytes; and answer the following questions for each organism: a  Who sequenced this organism’s genome, and in what year was it completed? b What is the size of each organism’s genome in base pairs? c Approximately how many genes are in each genome? d Briefly describe why geneticists are interested in studying this organism’s genome Exercise II – Exploring the Genomes of Model Organisms A tremendous amount of information is available about the genomes of the many model organisms that have played invaluable roles in advancing our understanding of genetics Following are links to several sites that are excellent resources for you as you study genetics Visit the site for links to information about your favorite Summary Points Mendel’s work on pea plants established the principles of gene transmission from parents to offspring that form the foundation for the science of genetics Genes and chromosomes are the fundamental units in the chromosomal theory of inheritance This theory explains that inherited traits are controlled by genes located on chromosomes and shows how the transmission of genetic information maintains genetic continuity from generation to generation Molecular genetics—based on the central dogma that DNA is a template for making RNA, which encodes the order of amino acids in proteins—explains the phenomena described by Mendelian genetics, referred to as transmission genetics Recombinant DNA technology, a far-reaching methodology used in molecular genetics, allows genes from one organism to be spliced into vectors and cloned, producing many copies of specific DNA sequences Biotechnology has revolutionized agriculture, the pharmaceutical industry, and medicine It has made possible the mass M01_KLUG7260_11_GE_C01.indd 48 model organism to learn more about its genome! • Ensembl Genome Browser: www ensembl.org/index.html Outstanding site for genome information on many model organisms • FlyBase: flybase.org Great database on Drosophila genes and genomes • Gold™ Genomes OnLine Database: www.genomesonline.org Comprehensive access to completed and ongoing genome projects worldwide • Model Organisms for Biomedical Research: www.nih.gov/science/ models National Institutes of Health site with a wealth of resources on model organisms • The Arabidopsis Information Resource: www.arabidopsis.org Genetic database for the model plant Arabidopsis thaliana • WormBase: www.wormbase.org Genome database for the nematode roundworm Caenorhabditis elegans For activities, animations, and review quizzes, go to the Study Area production of medically important gene products Genetic testing allows detection of individuals with genetic disorders and those at risk of having affected children, and gene therapy offers hope for the treatment of serious genetic disorders Genomics, proteomics, and bioinformatics are new fields derived from recombinant DNA technology These fields combine genetics with information technology and allow scientists to explore genome sequences, the structure and function of genes, the protein set within cells, and the evolution of genomes The Human Genome Project is one example of genomics The use of model organisms has advanced the understanding of genetic mechanisms and, coupled with recombinant DNA technology, has produced models of human genetic diseases The effects of genetic technology on society are profound, and the development of policy and legislation to deal with issues derived from the use of this technology is lagging behind the resulting innovations 14/08/15 2:46 PM www.downloadslide.com Proble ms and Di s c u s s io n Q u es t i o n s Ca s e Study T Extending essential ideas of genetics beyond the classroom o make genetics relevant to situations that you may encounter outside the classroom, each chapter will contain a short case study accompanied by questions Each case is designed to draw attention to one of the basic concepts covered in the chapter The case is designed to draw attention to one of the basic concepts covered in the chapter The case uses examples and scenarios to illustrate Problems and Discussion Questions How does Mendel’s work on the transmission of traits relate to our understanding of genetics today? C ON C EPT Q UESTION Review the Chapter Concepts list on p 35 Most of these are related to the discovery of DNA as the genetic material and the subsequent development of recombinant DNA technology Write a brief essay that discusses the impact of recombinant DNA technology on genetics as we perceive the discipline today What is the chromosome theory of inheritance, and how is it related to Mendel’s findings? Define genotype and phenotype Describe how they are related and how alleles fit into your definitions Given the state of knowledge at the time of the Avery, MacLeod, and McCarty experiment, why was it difficult for some scientists to accept that DNA is the carrier of genetic information? What is a gene? What is the structure of DNA? How does it differ from that of RNA? Describe the central dogma of molecular genetics and how it serves as the basis of modern genetics Until the mid-1940s, many scientists considered proteins to be the likely candidates for the genetic material Why? 10 Outline the roles played by restriction enzymes and vectors in cloning DNA 11 Genetics is commonly seen as being grouped into several general areas: transmission, molecular, and population/evolution Which biological processes are studied in transmission genetics? 12 Summarize the arguments for and against patenting genetically modified organisms 13 We all carry about 20,000 genes in our genome So far, patents have been issued for more than 6000 of these genes Do you think that companies or individuals should be able to patent human genes? Why or why not? M01_KLUG7260_11_GE_C01.indd 49 49 how this concept can be applied to genetic issues in everyday life Many of the case studies and their accompanying questions can serve as the basis of classroom discussions, group projects, or as starting points for papers and presentations Use these resources to enhance your learning experience and to bring genetics out of the book and into your life Visit for instructor-assigned tutorials and problems 14 Why we use model organisms to study human genetic diseases? 15 If you knew that a devastating late-onset inherited disease runs in your family (in other words, a disease that does not appear until later in life) and you could be tested for it at the age of 20, would you want to know whether you are a carrier? Would your answer be likely to change when you reach age 40? 16 Why you think discoveries in genetics have been recognized with so many Nobel Prizes? 17 The Age of Genetics was created by remarkable advances in the use of biotechnology to manipulate plant and animal genomes Given that the world population has topped billion and is expected to reach 9.2 billion by 2050, some scientists have proposed that only the worldwide introduction of genetically modified (GM) foods will increase crop yields enough to meet future nutritional demands Pest resistance, herbicide, cold, drought, and salinity tolerance, along with increased nutrition, are seen as positive attributes of GM foods However, others caution that unintended harm to other organisms, reduced effectiveness to pesticides, gene transfer to nontarget species, allergenicity, and as yet unknown effects on human health are potential concerns regarding GM foods If you were in a position to control the introduction of a GM primary food product (rice, for example), what criteria would you establish before allowing such introduction? 18 Why have the advances in bioinformatics kept pace with the advances in biotechnology, while the policies and legislation regarding the ethical issues involved have lagged behind? 14/08/15 2:46 PM www.downloadslide.com Chromosomes in the prometaphase stage of mitosis, derived from a cell in the flower of Haemanthus Mitosis and Meiosis Chapter Concepts ■ Genetic continuity between generations of cells and between generations of sexually reproducing organisms is maintained through the processes of mitosis and meiosis, respectively ■ Diploid eukaryotic cells contain their genetic information in pairs of homologous chromosomes, with one member of each pair being derived from the maternal parent and one from the paternal parent ■ Mitosis provides a mechanism by which chromosomes, having been duplicated, are distributed into progeny cells during cell reproduction ■ Mitosis converts a diploid cell into two diploid daughter cells ■ The process of meiosis distributes one member of each homologous pair of chromosomes into each gamete or spore, thus reducing the diploid chromosome number to the haploid chromosome number ■ Meiosis generates genetic variability by distributing various combinations of maternal and paternal members of each homologous pair of chromosomes into gametes or spores ■ During the stages of mitosis and meiosis, the genetic material is condensed into discrete structures called chromosomes E very living thing contains a substance described as the genetic material Except in certain viruses, this material is composed of the nucleic acid DNA DNA has an underlying linear structure possessing segments called genes, the products of which direct the metabolic activities of cells An organism’s DNA, with its arrays of genes, is organized into structures called chromosomes, which serve as vehicles for transmitting genetic information The manner in which chromosomes are transmitted from one generation of cells to the next and from organisms to their descendants must be exceedingly precise In this chapter we consider exactly how genetic continuity is maintained between cells and organisms Two major processes are involved in the genetic continuity of nucleated cells: mitosis and meiosis Although the mechanisms of the two processes are similar in many ways, the outcomes are quite different Mitosis leads to the production of two cells, each with the same number of chromosomes as the parent cell In contrast, meiosis reduces the genetic content and the number of chromosomes by precisely half This reduction is essential if sexual reproduction is to occur without doubling the amount of genetic material in each new generation Strictly speaking, mitosis is that portion of the cell cycle during which the hereditary components are equally partitioned into daughter cells Meiosis is part of a special type of cell division that leads to the production of sex cells: gametes or spores This process is an essential step in the transmission of genetic information from an organism to its offspring 50 M02_KLUG7260_11_GE_C02.indd 50 14/08/15 3:01 PM www.downloadslide.com 2.1 C e ll S tructu re Is C lose ly Tie d to G e ne t ic Fu nc t io n Normally, chromosomes are visible only during mitosis and meiosis When cells are not undergoing division, the genetic material making up chromosomes unfolds and uncoils into a diffuse network within the nucleus, generally referred to as chromatin Before describing mitosis and meiosis, we will briefly review the structure of cells, emphasizing components that are of particular significance to genetic function We will also compare the structural differences between the prokaryotic (nonnucleated) cells of bacteria and the eukaryotic cells of higher organisms We then devote the remainder of the chapter to the behavior of chromosomes during cell division 2.1 Cell Structure Is Closely Tied to Genetic Function Before 1940, our knowledge of cell structure was limited to what we could see with the light microscope Around 1940, the transmission electron microscope was in its early stages of development, and by 1950, many details of cell 51 ultrastructure had emerged Under the electron microscope, cells were seen as highly varied, highly organized structures whose form and function are dependent on specific genetic expression by each cell type A new world of whorled membranes, organelles, microtubules, granules, and filaments was revealed These discoveries revolutionized thinking in the entire field of biology Many cell components, such as the nucleolus, ribosome, and centriole, are involved directly or indirectly with genetic processes Other components— the mitochondria and chloroplasts—contain their own unique genetic information Here, we will focus primarily on those aspects of cell structure that relate to genetic study The generalized animal cell shown in Figure 2–1 illustrates most of the structures we will discuss All cells are surrounded by a plasma membrane, an outer covering that defines the cell boundary and delimits the cell from its immediate external environment This membrane is not passive but instead actively controls the movement of materials into and out of the cell In addition to this membrane, plant cells have an outer covering called the cell wall whose major component is a polysaccharide called cellulose Nucleus Bound ribosome Nuclear envelope Rough endoplasmic reticulum Nucleolus Chromatin Plasma membrane Nuclear pore Lysosome Glycocalyx Smooth endoplasmic reticulum Cytoplasm Free ribosome Golgi body Centriole Figure 2–1 M02_KLUG7260_11_GE_C02.indd 51 Mitochondrion   A generalized animal cell The cellular components discussed in the text are emphasized here 14/08/15 3:01 PM www.downloadslide.com 52 Mito sis an d Meio sis Many, if not most, animal cells have a covering over the plasma membrane, referred to as the glycocalyx, or cell coat Consisting of glycoproteins and polysaccharides, this covering has a chemical composition that differs from comparable structures in either plants or bacteria The glycocalyx, among other functions, provides biochemical identity at the surface of cells, and the components of the coat that establish cellular identity are under genetic control For example, various cell-identity markers that you may have heard of—the AB, Rh, and MN antigens—are found on the surface of red blood cells, among other cell types On the surface of other cells, histocompatibility antigens, which elicit an immune response during tissue and organ transplants, are present Various receptor molecules are also found on the surfaces of cells These molecules act as recognition sites that transfer specific chemical signals across the cell membrane into the cell Living organisms are categorized into two major groups depending on whether or not their cells contain a nucleus The presence of a nucleus and other membranous organelles is the defining characteristic of eukaryotic organisms The nucleus in eukaryotic cells is a membrane-bound structure that houses the genetic material, DNA, which is complexed with an array of acidic and basic proteins into thin fibers During nondivisional phases of the cell cycle, the fibers are uncoiled and dispersed into chromatin (as mentioned above) During mitosis and meiosis, chromatin fibers coil and condense into chromosomes Also present in the nucleus is the nucleolus, an amorphous component where ribosomal RNA (rRNA) is synthesized and where the initial stages of ribosomal assembly occur The portions of DNA that encode rRNA are collectively referred to as the nucleolus organizer region, or the NOR Prokaryotic organisms, of which there are two major groups, lack a nuclear envelope and membranous organelles For the purpose of our brief discussion here, we will consider the eubacteria, the other group being the more ancient bacteria referred to as archaea In eubacteria, such as Escherichia coli, the genetic material is present as a long, circular DNA molecule that is compacted into an unenclosed region called the nucleoid Part of the DNA may be attached to the cell membrane, but in general the nucleoid extends through a large part of the cell Although the DNA is compacted, it does not undergo the extensive coiling characteristic of the stages of mitosis, during which the chromosomes of eukaryotes become visible Nor is the DNA associated as extensively with proteins as is eukaryotic DNA Figure 2–2, which shows two bacteria forming by cell division, illustrates the nucleoid regions containing the bacterial chromosomes Prokaryotic cells not have a distinct nucleolus but contain genes that specify rRNA molecules M02_KLUG7260_11_GE_C02.indd 52 Nucleoid regions Figur e 2–2   Color-enhanced electron micrograph of E coli undergoing cell division Particularly prominent are the two chromosomal areas (shown in red), called nucleoids, that have been partitioned into the daughter cells The remainder of the eukaryotic cell within the plasma membrane, excluding the nucleus, is referred to as cytoplasm and includes a variety of extranuclear cellular organelles In the cytoplasm, a nonparticulate, colloidal material referred to as the cytosol surrounds and encompasses the cellular organelles The cytoplasm also includes an extensive system of tubules and filaments, comprising the cytoskeleton, which provides a lattice of support structures within the cell Consisting primarily of microtubules, which are made of the protein tubulin, and microfilaments, which derive from the protein actin, this structural framework maintains cell shape, facilitates cell mobility, and anchors the various organelles One organelle, the membranous endoplasmic reticulum (ER), compartmentalizes the cytoplasm, greatly increasing the surface area available for biochemical synthesis The ER appears smooth in places where it serves as the site for synthesizing fatty acids and phospholipids; in other places, it appears rough because it is studded with ribosomes Ribosomes serve as sites where genetic information contained in messenger RNA (mRNA) is translated into proteins Three other cytoplasmic structures are very important in the eukaryotic cell’s activities: mitochondria, chloroplasts, and centrioles Mitochondria are found in most eukaryotes, including both animal and plant cells, and are the sites of the oxidative phases of cell respiration These chemical reactions generate large amounts of the energy-rich molecule adenosine triphosphate (ATP) Chloroplasts, which are found in plants, algae, and some protozoans, are associated with photosynthesis, the major energy-trapping process on Earth Both mitochondria and chloroplasts contain DNA in a form distinct from that found in the nucleus They are able to duplicate themselves 14/08/15 3:01 PM www.downloadslide.com 2.2 C hromo some s Ex is t in Hom olo gou s Pai rs in Dip loid Organ isms and transcribe and translate their own genetic information It is interesting to note that the genetic machinery of mitochondria and chloroplasts closely resembles that of prokaryotic cells This and other observations have led to the proposal that these organelles were once primitive free-living organisms that established symbiotic relationships with primitive eukaryotic cells This theory concerning the evolutionary origin of these organelles is called the endosymbiont hypothesis Animal cells and some plant cells also contain a pair of complex structures called centrioles These cytoplasmic bodies, each located in a specialized region called the centrosome, are associated with the organization of spindle fibers that function in mitosis and meiosis In some organisms, the centriole is derived from another structure, the basal body, which is associated with the formation of cilia and flagella (hair-like and whip-like structures for propelling cells or moving materials) The organization of spindle fibers by the centrioles occurs during the early phases of mitosis and meiosis These fibers play an important role in the movement of chromosomes as they separate during cell division They are composed of arrays of microtubules consisting of polymers of the protein tubulin 53 arm ratios are produced As Figure 2–3 illustrates, chromosomes are classified as metacentric, submetacentric, acrocentric, or telocentric on the basis of the centromere location The shorter arm, by convention, is shown above the centromere and is called the p arm (p, for “petite”) The longer arm is shown below the centromere and is called the q arm (q because it is the next letter in the alphabet) In the study of mitosis, several other observations are of particular relevance First, all somatic cells derived from members of the same species contain an identical number of chromosomes In most cases, this represents the diploid number (2n), whose meaning will become clearer below When the lengths and centromere placements of all such chromosomes are examined, a second general feature is apparent With the exception of sex chromosomes, they exist in pairs with regard to these two properties, and the members of each pair are called homologous chromosomes So, for each chromosome exhibiting a specific length and centromere placement, another exists with identical features There are exceptions to this rule Many bacteria and viruses have but one chromosome, and organisms such as yeasts and molds, and certain plants such as bryophytes (mosses), spend the predominant phase of their life cycle in the haploid stage That is, they contain only one member 2.2 Chromosomes Exist in Homologous Pairs in Diploid Organisms As we discuss the processes of mitosis and meiosis, it is important that you understand the concept of homologous chromosomes Such an understanding will also be of critical importance in our future discussions of Mendelian genetics Chromosomes are most easily visualized during mitosis When they are examined carefully, distinctive lengths and shapes are apparent Each chromosome contains a constricted region called the centromere, whose location establishes the general appearance of each chromosome Figure 2–3 shows chromosomes with centromere placements at different distances along their length Extending from either side of the centromere are the arms of the chromosome Depending on the position of the centromere, different M02_KLUG7260_11_GE_C02.indd 53 Centromere location Designation Middle Metacentric Metaphase shape Sister chromatids Anaphase shape Centromere Migration p arm Between middle and end Submetacentric Close to end Acrocentric At end Telocentric q arm Figur e 2–3   Centromere locations and the chromosome designations that are based on them Note that the shape of the chromosome during anaphase is determined by the position of the centromere during metaphase 14/08/15 3:01 PM www.downloadslide.com 54 Mito sis an d Meio sis F i g u r e –   A metaphase preparation of chromosomes derived from a dividing cell of a human male (left), and the karyotype derived from the metaphase preparation (right) All but the X and Y chromosomes are present in homologous pairs Each chromosome is clearly a double structure consisting of a pair of sister chromatids joined by a common centromere of each homologous pair of chromosomes during most of their lives Figure 2–4 illustrates the physical appearance of different pairs of homologous chromosomes There, the human mitotic chromosomes have been photographed, cut out of the print, and matched up, creating a display called a karyotype As you can see, humans have a 2n number of 46 chromosomes, which on close examination exhibit a diversity of sizes and centromere placements Note also that each of the 46 chromosomes in this karyotype is clearly a double structure consisting of two parallel sister chromatids connected by a common centromere Had these chromosomes been allowed to continue dividing, the sister chromatids, which are replicas of one another, would have separated into the two new cells as division continued The haploid number (n) of chromosomes is equal to one-half the diploid number Collectively, the genetic information contained in a haploid set of chromosomes constitutes the genome of the species This, of course, includes copies of all genes as well as a large amount of noncoding DNA The examples listed in Table 2.1 demonstrate the wide range of n values found in plants and animals Homologous chromosomes have important genetic similarities They contain identical gene sites along their lengths; each site is called a locus (pl loci) Thus, they are identical in the traits that they influence and in their genetic potential In sexually reproducing organisms, one member of each pair is derived from the maternal parent (through the ovum) and the other member is derived from the paternal parent (through the sperm) Therefore, each diploid organism contains two copies of each gene as a M02_KLUG7260_11_GE_C02.indd 54 consequence of biparental inheritance, inheritance from two parents As we shall see in the chapters on transmission genetics, the members of each pair of genes, while influencing the same characteristic or trait, need not be identical In a population of members of the same species, many different alternative forms of the same gene, called alleles, can exist The concepts of haploid number, diploid number, and homologous chromosomes are important for understanding the process of meiosis During the formation of gametes or spores, meiosis converts the diploid number of chromosomes to the haploid number As a result, haploid gametes or spores contain precisely one member of each homologous pair of chromosomes—that is, one complete haploid set Following fusion of two gametes at fertilization, the diploid number is reestablished; that is, the zygote contains two complete haploid sets of chromosomes The constancy of genetic material is thus maintained from generation to generation There is one important exception to the concept of homologous pairs of chromosomes In many species, one pair, consisting of the sex-determining chromosomes, is often not homologous in size, centromere placement, arm ratio, or genetic content For example, in humans, while females carry two homologous X chromosomes, males carry one Y chromosome in addition to one X chromosome (Figure 2–4) These X and Y chromosomes are not strictly homologous The Y is considerably smaller and lacks most of the gene loci contained on the X Nevertheless, they contain homologous regions and behave as homologs in meiosis so that gametes produced by males receive either one X or one Y chromosome 14/08/15 3:01 PM www.downloadslide.com 2.3 Mitosis Partitions C hromosome s into Di vi d i n g Cel l s Tab l e   The Haploid Number of Chromosomes for a Variety of Organisms Common Name Scientific Name Black bread mold Broad bean Cat Cattle Chicken Chimpanzee Corn Cotton Dog Evening primrose Frog Fruit fly Garden onion Garden pea Grasshopper Green alga Horse House fly House mouse Human Jimson weed Mosquito Mustard plant Pink bread mold Potato Rhesus monkey Roundworm Silkworm Slime mold Snapdragon Tobacco Tomato Water fly Wheat Yeast Zebrafish Aspergillus nidulans Vicia faba Felis domesticus Bos taurus Gallus domesticus Pan troglodytes Zea mays Gossypium hirsutum Canis familiaris Oenothera biennis Rana pipiens Drosophila melanogaster Allium cepa Pisum sativum Melanoplus differentialis Chlamydomonas reinhardtii Equus caballus Musca domestica Mus musculus Homo sapiens Datura stramonium Culex pipiens Arabidopsis thaliana Neurospora crassa Solanum tuberosum Macaca mulatta Caenorhabditis elegans Bombyx mori Dictyostelium discoideum Antirrhinum majus Nicotiana tabacum Lycopersicon esculentum Nymphaea alba Triticum aestivum Saccharomyces cerevisiae Danio rerio Haploid Number 19 30 39 24 10 26 39 13 12 18 32 20 23 12 24 21 28 24 12 80 21 16 25 55 the intestinal lining of humans are continuously sloughed off and replaced Cell division also results in the continuous production of reticulocytes that eventually shed their nuclei and replenish the supply of red blood cells in vertebrates In abnormal situations, somatic cells may lose control of cell division, and form a tumor The genetic material is partitioned into daughter cells during nuclear division, or karyokinesis This process is quite complex and requires great precision The chromosomes must first be exactly replicated and then accurately partitioned The end result is the production of two daughter nuclei, each with a chromosome composition identical to that of the parent cell Karyokinesis is followed by cytoplasmic division, or cytokinesis This less complex process requires a mechanism that partitions the volume into two parts, then encloses each new cell in a distinct plasma membrane As the cytoplasm is reconstituted, organelles replicate themselves, arise from existing membrane structures, or are synthesized de novo (anew) in each cell Following cell division, the initial size of each new daughter cell is approximately one-half the size of the parent cell However, the nucleus of each new cell is not appreciably smaller than the nucleus of the original cell Quantitative measurements of DNA confirm that there is an amount of genetic material in the daughter nuclei equivalent to that in the parent cell Interphase and the Cell Cycle Many cells undergo a continuous alternation between division and nondivision The events that occur from the completion of one division until the completion of the next division constitute the cell cycle (Figure 2–5) S phase G1 Interphase G2 G0 2.3 Mitosis Partitions Chromosomes into Dividing Cells The process of mitosis is critical to all eukaryotic organisms In some single-celled organisms, such as protozoans and some fungi and algae, mitosis (as a part of cell division) provides the basis for asexual reproduction Multicellular diploid organisms begin life as single-celled fertilized eggs called zygotes The mitotic activity of the zygote and the subsequent daughter cells is the foundation for the development and growth of the organism In adult organisms, mitotic activity is the basis for wound healing and other forms of cell replacement in certain tissues For example, the epidermal cells of the skin and M02_KLUG7260_11_GE_C02.indd 55 Mitosis Nondividing cells G1 Telophase Anaphase Prophase Prometaphase Metaphase Figur e 2–5  The stages comprising an arbitrary cell cycle Following mitosis, cells enter the G1 stage of interphase, initiating a new cycle Cells may become nondividing (G0) or continue through G1, where they become committed to begin DNA synthesis (S) and complete the cycle (G2 and mitosis) Following mitosis, two daughter cells are produced, and the cycle begins anew for both of them 14/08/15 3:01 PM www.downloadslide.com 56 Mitosis an d Meiosis We will consider interphase, the initial stage of the cell cycle, as the interval between divisions It was once thought that the biochemical activity during interphase was devoted solely to the cell’s growth and its normal function However, we now know that another biochemical step critical to the ensuing mitosis occurs during interphase: the replication of the DNA of each chromosome This period, during which DNA is synthesized, occurs before the cell enters mitosis and is called the S phase The initiation and completion of synthesis can be detected by monitoring the incorporation of radioactive precursors into DNA Investigations of this nature demonstrate two periods during interphase when no DNA synthesis occurs, one before and one after the S phase These are designated G1 (gap I) and G2 (gap II), respectively During both of these intervals, as well as during S, intensive metabolic activity, cell growth, and cell differentiation are evident By the end of G2, the volume of the cell has roughly doubled, DNA has been replicated, and mitosis (M) is initiated Following mitosis, continuously dividing cells then repeat this cycle (G1, S, G2, M) over and over, as shown in Figure 2–5 Much is known about the cell cycle based on in vitro (literally, “in glass”) studies When grown in culture, many cell types in different organisms traverse the complete cycle in about 16 hours The actual process of mitosis occupies only a small part of the overall cycle, often less than an hour The lengths of the S and G2 phases of interphase are fairly consistent in different cell types Most variation is seen in the length of time spent in the G1 stage Figure 2–6 shows the relative length of these intervals as well as the length of the stages of mitosis in a human cell in culture G1 is of great interest in the study of cell proliferation and its control At a point during G1, all cells follow one of two paths They either withdraw from the cycle, become quiescent, and enter the G0 stage (see Interphase Mitosis G1 S G2 M Hours Pro Met Ana Tel 36 3 18 Minutes F i g u r e –  The time spent in each interval of one complete cell cycle of a human cell in culture Times vary according to cell types and conditions M02_KLUG7260_11_GE_C02.indd 56 Figure 2–5), or they become committed to proceed through G1, initiating DNA synthesis, and completing the cycle Cells that enter G0 remain viable and metabolically active but are not proliferative Cancer cells apparently avoid entering G0 or pass through it very quickly Other cells enter G0 and never reenter the cell cycle Still other cells in G0 can be stimulated to return to G1 and thereby reenter the cell cycle Cytologically, interphase is characterized by the absence of visible chromosomes Instead, the nucleus is filled with chromatin fibers that are formed as the chromosomes uncoil and disperse after the previous mitosis [Figure 2–7(a)] Once G1, S, and G2 are completed, mitosis is initiated Mitosis is a dynamic period of vigorous and continual activity For discussion purposes, the entire process is subdivided into discrete stages, and specific events are assigned to each one These stages, in order of occurrence, are prophase, prometaphase, metaphase, anaphase, and telophase They are diagrammed with corresponding photomicrographs in Figure 2–7 Prophase Often, over half of mitosis is spent in prophase [Figure 2–7(b)], a stage characterized by several significant occurrences One of the early events in prophase of all animal cells is the migration of two pairs of centrioles to opposite ends of the cell These structures are found just outside the nuclear envelope in an area of differentiated cytoplasm called the centrosome (introduced in Section 2.1) It is believed that each pair of centrioles consists of one mature unit and a smaller, newly formed daughter centriole The centrioles migrate and establish poles at opposite ends of the cell After migration, the centrosomes, in which the centrioles are localized, are responsible for organizing cytoplasmic microtubules into the spindle fibers that run between these poles, creating an axis along which chromosomal separation occurs Interestingly, the cells of most plants (there are a few exceptions), fungi, and certain algae seem to lack centrioles Spindle fibers are nevertheless apparent during mitosis As the centrioles migrate, the nuclear envelope begins to break down and gradually disappears In a similar fashion, the nucleolus disintegrates within the nucleus While these events are taking place, the diffuse chromatin fibers have begun to condense, until distinct threadlike structures, the chromosomes, become visible It becomes apparent near the end of prophase that each chromosome is actually a double structure split longitudinally except at a single point of constriction, the centromere The two parts of each chromosome are called sister chromatids because the DNA contained in each of them is genetically 14/08/15 3:01 PM www.downloadslide.com 2.3 57 Mitosis Pa rtition s C hromosom es into Di vi d i ng Cel l s (a) Interphase (b) Prophase (c) Prometaphase (d) Metaphase Chromosomes are extended and uncoiled, forming chromatin Chromosomes coil up and condense; centrioles divide and move apart Chromosomes are clearly double structures; centrioles reach the opposite poles; spindle fibers form Centromeres align on metaphase plate Cell plate Plant cell telophase (e) Anaphase (f) Telophase Centromeres split and daughter chromosomes migrate to opposite poles Daughter chromosomes arrive at the poles; cytokinesis commences F i g u r e –  Drawings depicting mitosis in an animal cell with a diploid number of The events occurring in each stage are described in the text Of the two homologous pairs of chromosomes, one pair consists of longer, metacentric members and the other of shorter, submetacentric members The maternal chromosome and the paternal chromosome of each pair are shown in different colors In (f), a drawing of late telophase in a plant cell shows the formation of the cell plate and lack of centrioles The cells shown in the light micrographs came from the flower of Haemanthus, a plant that has a diploid number of M02_KLUG7260_11_GE_C02.indd 57 14/08/15 3:01 PM www.downloadslide.com 58 Mito sis an d Meio sis identical, having formed from a single replicative event Sister chromatids are held together by a multi-subunit protein complex called cohesin This molecular complex is originally formed between them during the S phase of the cell cycle when the DNA of each chromosome is replicated Thus, even though we cannot see chromatids in interphase because the chromatin is uncoiled and dispersed in the nucleus, the chromosomes are already double structures, which becomes apparent in late prophase In humans, with a diploid number of 46, a cytological preparation of late prophase reveals 46 chromosomes randomly distributed in the area formerly occupied by the nucleus Prometaphase and Metaphase The distinguishing event of the two ensuing stages is the migration of every chromosome, led by its centromeric region, to the equatorial plane The equatorial plane, also referred to as the metaphase plate, is the midline region of the cell, a plane that lies perpendicular to the axis established by the spindle fibers In some descriptions, the term prometaphase refers to the period of chromosome movement [Figure 2–7(c)], and the term metaphase is applied strictly to the chromosome configuration following migration Migration is made possible by the binding of spindle fibers to the chromosome’s kinetochore, an assembly of multilayered plates of proteins associated with the centromere This structure forms on opposite sides of each paired centromere, in intimate association with the two sister chromatids Once properly attached to the spindle fibers, cohesin is degraded by an enzyme, appropriately named separase, and the sister chromatid arms disjoin, except at the centromere region A unique protein family called shugoshin (from the Japanese meaning guardian spirit) protects cohesin from being degraded by separase at the centromeric regions The involvement of the cohesin and shugoshin complexes with a pair of sister chromatids during mitosis is depicted in Figure 2–8 We know a great deal about the molecular interactions involved in kinetechore assembly along the centromere This is of great interest because of the consequences when mutations alter the proteins that make up the kinetechore complex Altered kinetechore function potentially leads to errors during chromosome migration, altering the diploid content of daughter cells A more detailed account will be presented later in the text, once we have provided more information about DNA and the proteins that make up chromatin (see Chapter 12) We also know a great deal about spindle fibers They consist of microtubules, which themselves consist of molecular subunits of the protein tubulin Microtubules seem to M02_KLUG7260_11_GE_C02.indd 58 Spindle fiber Kinetochore Sister chromatids Cohesin Centromere region Shugoshin Microtubule Figur e 2–8  The depiction of the alignment, pairing, and disjunction of sister chromatids during mitosis, involving the molecular complexes cohesin and shugoshin and the enzyme separase originate and “grow” out of the two centrosome regions at opposite poles of the cell They are dynamic structures that lengthen and shorten as a result of the addition or loss of polarized tubulin subunits The microtubules most directly responsible for chromosome migration make contact with, and adhere to, kinetochores as they grow from the centrosome region They are referred to as kinetochore microtubules and have one end near the centrosome region (at one of the poles of the cell) and the other end anchored to the kinetochore The number of microtubules that bind to the kinetochore varies greatly between organisms Yeast (Saccharomyces) has only a single microtubule bound to each plate-like structure of the kinetochore Mitotic cells of mammals, at the other extreme, reveal 30 to 40 microtubules bound to each portion of the kinetochore At the completion of metaphase, each centromere is aligned at the metaphase plate with the chromosome arms extending outward in a random array This configuration is shown in Figure 2–7(d) Anaphase Events critical to chromosome distribution during mitosis occur during anaphase, the shortest stage of mitosis During this phase, sister chromatids of each chromosome, held together only at their centromere regions, disjoin (separate) from one another—an event described as disjunction—and are pulled to opposite ends of the cell For complete disjunction to occur: (1) shugoshin must be degraded, reversing its protective role; (2) the cohesin complex holding the centromere region of each sister chromosome is then cleaved by separase; and (3) sister 14/08/15 3:01 PM www.downloadslide.com 2.3 Mitosis Partitions C hromosome s into Di vi d i n g Cel l s chromatids of each chromosome are pulled toward the opposite poles of the cell (Figure 2–8) As these events proceed, each migrating chromatid is now referred to as a daughter chromosome Movement of daughter chromosomes to the opposite poles of the cell is dependent on the kinetechore–spindle fiber attachment Recent investigations reveal that chromosome migration results from the activity of a series of specific molecules called motor proteins found at several locations within the dividing cell These proteins, described as molecular motors, use the energy generated by the hydrolysis of ATP Their effect on the activity of microtubules serves ultimately to shorten the spindle fibers, drawing the chromosomes to opposite ends of the cell The centromeres of each chromosome appear to lead the way during migration, with the chromosome arms trailing behind Several models have been proposed to account for the shortening of spindle fibers They share in common the selective removal of tubulin subunits at the ends of the spindle fibers The removal process is accomplished by the molecular motor proteins described above The location of the centromere determines the shape of the chromosome during separation, as you saw in Figure 2–3 The steps that occur during anaphase are critical in providing each subsequent daughter cell with an identical set of chromosomes In human cells, there would now be 46 chromosomes at each pole, one from each original sister pair Figure 2–7(e) shows anaphase prior to its completion Telophase Telophase is the final stage of mitosis and is depicted in Figure 2–7(f) At its beginning, two complete sets of chromosomes are present, one set at each pole The most significant event of this stage is cytokinesis, the division or partitioning of the cytoplasm Cytokinesis is essential if two new cells are to be produced from one cell The mechanism of cytokinesis differs greatly in plant and animal cells, but the end result is the same: two new cells are produced In plant cells, a cell plate is synthesized and laid down across the region of the metaphase plate Animal cells, however, undergo a constriction of the cytoplasm, much as a loop of string might be tightened around the middle of a balloon It is not surprising that the process of cytokinesis varies in different organisms Plant cells, which are more regularly shaped and structurally rigid, require a mechanism for depositing new cell wall material around the plasma membrane The cell plate laid down during telophase becomes a structure called the middle lamella Subsequently, the primary and secondary layers of the cell wall are deposited M02_KLUG7260_11_GE_C02.indd 59 59 between the cell membrane and middle lamella in each of the resulting daughter cells In animals, complete constriction of the cell membrane produces the cell furrow characteristic of newly divided cells Other events necessary for the transition from mitosis to interphase are initiated during late telophase They generally constitute a reversal of events that occurred during prophase In each new cell, the chromosomes begin to uncoil and become diffuse chromatin once again, while the nuclear envelope reforms around them, the spindle fibers disappear, and the nucleolus gradually reforms and becomes visible in the nucleus during early interphase At the completion of telophase, the cell enters interphase Cell-Cycle Regulation and Checkpoints The cell cycle, culminating in mitosis, is fundamentally the same in all eukaryotic organisms This similarity in many diverse organisms suggests that the cell cycle is governed by a genetically regulated program that has been conserved throughout evolution Because disruption of this regulation may underlie the uncontrolled cell division characterizing malignancy, interest in how genes regulate the cell cycle is particularly strong A mammoth research effort over the past 20 years has paid high dividends, and we now have knowledge of many genes involved in the control of the cell cycle This work was recognized by the awarding of the 2001 Nobel Prize in Medicine or Physiology to Lee Hartwell, Paul Nurse, and Tim Hunt As with other studies of genetic control over essential biological processes, investigation has focused on the discovery of mutations that interrupt the cell cycle and on the effects of those mutations As we shall return to this subject in much greater detail later in the text during our consideration of the molecular basis of cancer (see Chapter 19), what follows is a very brief overview Many mutations are now known that exert an effect at one or another stage of the cell cycle First discovered in yeast, but now evident in all organisms, including humans, such mutations were originally designated as cell division cycle (cdc) mutations The normal products of many of the mutated genes are enzymes called kinases that can add phosphates to other proteins They serve as “master control” molecules functioning in conjunction with proteins called cyclins Cyclins bind to these kinases (creating cyclin-dependent kinases), activating them at appropriate times during the cell cycle Activated kinases then phosphorylate other target proteins that regulate the progress of the cell cycle The study of cdc mutations has established that the cell cycle contains at least three major checkpoints, where the processes culminating in normal mitosis are monitored, or “checked,” by these master 14/08/15 3:01 PM www.downloadslide.com 60 Mitosis an d Meiosis control molecules before the next stage of the cycle is allowed to commence Checkpoints are named according to where in the cell cycle monitoring occurs (Figure 2–5) The first of three (sometimes considered as two separate checkpoints), the G1/S checkpoint, monitors the size the cell has achieved since its previous mitosis and also evaluates the condition of the DNA If the cell has not reached an adequate size or if the DNA has been damaged, further progress through the cycle is arrested until these conditions are “corrected.” If both conditions are “normal” at G1/S, then the cell is allowed to proceed from G1 to the S phase of the cycle The second checkpoint is the G2/M checkpoint, where DNA is monitored prior to the start of mitosis If DNA replication is incomplete or any DNA damage is detected and has not been repaired, the cell cycle is arrested The final checkpoint occurs during mitosis and is called the M checkpoint (sometimes referred to as the Spindle Assembly checkpoint) Here, both the successful formation of the spindle fiber system and the attachment of spindle fibers to the kinetochores associated with the centromeres are monitored If spindle fibers are not properly formed or if attachment is inadequate, mitosis is arrested The importance of cell-cycle control and these checkpoints can be demonstrated by considering what happens when this regulatory system is impaired Let’s assume, for example, that the DNA of a cell has incurred damage leading to one or more mutations impairing cell-cycle control If allowed to proceed through the cell cycle as one of the population of dividing cells, this genetically altered cell would divide uncontrollably—a key step in the development of a cancer cell If instead the cell cycle is arrested at one of the checkpoints, the cell can repair the DNA damage or permanently stop the cell from dividing, thereby preventing its potential malignancy 2–1 With the initial appearance of the feature we call “Now Solve This,” a short introduction is in order The feature occurs several times in this and all ensuing chapters, each time providing a problem related to the discussion just presented A “Hint” is then offered that may help you solve the problem Here is the first problem: (a) If an organism has a diploid number of 16, how many chromatids are visible at the end of mitotic prophase? (b) How many chromosomes are moving to each pole during anaphase of mitosis? Hint: This problem involves an understanding of what happens to each pair of homologous chromosomes during mitosis, asking you to apply your understanding of chromosome behavior to an organism with a diploid number of 16 The key to its solution is your awareness that throughout mitosis, the members of each homologous pair not pair up, but instead behave independently M02_KLUG7260_11_GE_C02.indd 60 2.4 Meiosis Reduces the Chromosome Number from Diploid to Haploid in Germ Cells and Spores The process of meiosis, unlike mitosis, reduces the amount of genetic material by one-half Whereas in diploids mitosis produces daughter cells with a full diploid complement, meiosis produces gametes or spores with only one haploid set of chromosomes During sexual reproduction, gametes then combine through fertilization to reconstitute the diploid complement found in parental cells Figure 2–9 compares the two processes by following two pairs of homologous chromosomes The events of meiosis must be highly specific since by definition, haploid gametes or spores contain precisely one member of each homologous pair of chromosomes If successfully completed, meiosis ensures genetic continuity from generation to generation The process of sexual reproduction also ensures genetic variety among members of a species As you study meiosis, you will see that this process results in gametes that each contain unique combinations of maternally and paternally derived chromosomes in their haploid complement With such a tremendous genetic variation among the gametes, a huge number of maternal-paternal chromosome combinations are possible at fertilization Furthermore, you will see that the meiotic event referred to as crossing over results in genetic exchange between members of each homologous pair of chromosomes This process creates intact chromosomes that are mosaics of the maternal and paternal homologs from which they arise, further enhancing the potential genetic variation in gametes and the offspring derived from them Sexual reproduction therefore reshuffles the genetic material, producing offspring that often differ greatly from either parent Thus, meiosis is the major source of genetic recombination within species An Overview of Meiosis In the preceding discussion, we established what might be considered the goal of meiosis: the reduction to the haploid complement of chromosomes Before considering the phases of this process systematically, we will briefly summarize how diploid cells give rise to haploid gametes or spores You should refer to the right-hand side of Figure 2–9 during the following discussion We have established that in mitosis each paternally and maternally derived member of any given homologous pair of chromosomes behaves autonomously during division By contrast, early in meiosis, homologous 14/08/15 3:01 PM www.downloadslide.com 2.4 61 Me io sis R ed uc es the C hrom osome Nu mbe r fro m Dip loid to Haploi d in G e rm C e lls a n d Sp o r es Meiosis I Mitosis Diploid cell (2n = 4) Prometaphase Prophase I (synapsis) Sister chromatids Tetrad Metaphase (four chromosomes, each consisting of a pair of sister chromatids) Metaphase (two tetrads) Reductional division Anaphase Telophase Dyads Daughter cell (2n) Daughter cell (2n) Meiosis II Equational division Monads Gametes (n) F i g u r e –  Overview of the major events and outcomes of mitosis and meiosis As in Figure 2–7, two pairs of homologous chromosomes are followed chromosomes form pairs; that is, they synapse (or undergo synapsis) Each synapsed structure, initially called a bivalent, eventually gives rise to a tetrad consisting of four chromatids The presence of four chromatids demonstrates that both homologs (making up the bivalent) M02_KLUG7260_11_GE_C02.indd 61 have, in fact, duplicated Therefore, to achieve haploidy, two divisions are necessary The first division occurs in meiosis I and is described as a reductional division (because the number of centromeres, each representing one chromosome, is reduced by one-half) Components 14/08/15 3:01 PM www.downloadslide.com 62 Mito sis an d Meio sis of each tetrad—representing the two homologs—separate, yielding two dyads Each dyad is composed of two sister chromatids joined at a common centromere The second division occurs during meiosis II and is described as an equational division (because the number of centromeres remains equal) Here each dyad splits into two monads of one chromosome each Thus, the two divisions potentially produce four haploid cells Meiotic prophase I Leptonema Chromomeres Zygonema Bivalent Pachynema Tetrad Diplonema Chiasma Diakinesis Terminalization The First Meiotic Division: Prophase I We turn now to a detailed account of meiosis Like mitosis, meiosis is a continuous process We assign names to its stages and substages only to facilitate discussion From a genetic standpoint, three events characterize the initial stage, prophase I (Figure 2–10) First, as in mitosis, chromatin present in interphase thickens and coils into visible chromosomes And, as in mitosis, each chromosome is a double structure, held together by the molecular complex called cohesin Second, unlike mitosis, members of each homologous pair of chromosomes pair up, undergoing synapsis Third, crossing over occurs between chromatids of synapsed homologs Because of the complexity of these genetic events, this stage of meiosis is divided into five substages: leptonema, zygonema, pachynema, diplonema,* and diakinesis As we discuss these substages, be aware that, even though it is not immediately apparent in the earliest phases of meiosis, the DNA of chromosomes has been replicated during the prior interphase Leptonema  During the leptotene stage, the interphase chromatin material begins to condense, and the chromosomes, though still extended, become visible Along each chromosome are chromomeres, localized condensations that resemble beads on a string Evidence suggests that a process called homology search, which precedes and is essential to the initial pairing of homologs, begins during leptonema Zygonema  The chromosomes continue to shorten and thicken during the zygotene stage During the process of homology search, homologous chromosomes undergo initial alignment with one another This so-called rough pairing is complete by the end of zygonema In yeast, homologs are separated by about 300 nm, and near the end of zygonema, structures called lateral elements are visible between paired homologs As meiosis proceeds, the overall length of the lateral elements along the chromosome increases, and a more extensive ultrastructural component called the synaptonemal complex begins to form between the homologs This complex is believed to be the vehicle responsible for proper alignment during the pairing of homologs In some *These are the noun forms of these substages The adjective forms (leptotene, zygotene, pachytene, and diplotene) are also used in the text M02_KLUG7260_11_GE_C02.indd 62 Figur e 2–10  The substages of meiotic prophase I for the chromosomes depicted in Figure 2–9 14/08/15 3:01 PM www.downloadslide.com 2.4 Meiosis Red uces the C hromosome Nu mbe r from Diploid to Haploid in G e rm C e lls a n d S p o r es diploid organisms, this synapsis occurs in a zipper-like fashion, beginning at the ends of chromosomes attached to the nuclear envelope It is upon completion of zygonema that the paired homologs are referred to as bivalents Although both members of each bivalent have already replicated their DNA, it is not yet visually apparent that each member is a double structure The number of bivalents in each species is equal to the haploid (n) number Pachynema  In the transition from the zygotene to the pachytene stage, the chromosomes continue to coil and shorten, and further development of the synaptonemal complex occurs between the two members of each bivalent This leads to synapsis, a more intimate pairing Compared to the rough-pairing characteristic of zygonema, homologs are now separated by only 100 nm During pachynema, each homolog is now evident as a double structure, providing visual evidence of the earlier replication of the DNA of each chromosome Thus, each bivalent contains four chromatids As in mitosis, replicates are called sister chromatids, whereas chromatids from maternal and paternal members of a homologous pair are called nonsister chromatids The four-membered structure, also referred to as a tetrad, contains two pairs of sister chromatids Diplonema  During the ensuing diplotene stage, it is even more apparent that each tetrad consists of two pairs of sister chromatids Within each tetrad, each pair of sister chromatids begins to separate However, one or more areas remain in contact where chromatids are intertwined Each such area, called a chiasma (pl chiasmata), is thought to represent a point where nonsister chromatids have undergone genetic exchange through the process referred to above as crossing over Although the physical exchange between chromosome areas occurred during the previous pachytene stage, the result of crossing over is visible only when the duplicated chromosomes begin to separate Crossing over is an important source of genetic variability, and as indicated earlier, new combinations of genetic material are formed during this process Diakinesis  The final stage of prophase I is diakinesis The chromosomes pull farther apart, but nonsister chromatids remain loosely associated at the chiasmata As separation proceeds, the chiasmata move toward the ends of the tetrad This process of terminalization begins in late diplonema and is completed during diakinesis During this final substage, the nucleolus and nuclear envelope break down, and the two centromeres of each tetrad attach to the recently formed spindle fibers By the completion of prophase I, the centromeres of each tetrad structure are present on the metaphase plate of the cell M02_KLUG7260_11_GE_C02.indd 63 63 Metaphase, Anaphase, and Telophase I The remainder of the meiotic process is depicted in Figure 2–11 After meiotic prophase I, stages similar to those of mitosis occur In the first division, metaphase I, the chromosomes have maximally shortened and thickened The terminal chiasmata of each tetrad are visible and appear to be the major factor holding the nonsister chromatids together Each tetrad interacts with spindle fibers, facilitating its movement to the metaphase plate The alignment of each tetrad prior to the first anaphase is random: Half of the tetrad (one of the dyads) will subsequently be pulled to one or the other pole, and the other half moves to the opposite pole During the stages of meiosis I, a single centromeric region holds each pair of sister chromatids together It appears as a single unit, and a kinetechore forms around each one As in our discussion of mitosis (see Figure 2–8), cohesin plays the major role in keeping sister chromatids together At anaphase I, cohesin is degraded between sister chromatids, except at the centromere region, which, as in mitosis, is protected by a shugoshin complex Then, one-half of each tetrad (a dyad) is pulled toward each pole of the dividing cell This separation process is the physical basis of disjunction, the separation of homologous chromosomes from one another Occasionally, errors in meiosis occur and separation is not achieved The term nondisjunction describes such an error At the completion of the normal anaphase I, a series of dyads equal to the haploid number is present at each pole If crossing over had not occurred in the first meiotic prophase, each dyad at each pole would consist solely of either paternal or maternal chromatids However, the exchanges produced by crossing over create mosaic chromatids of paternal and maternal origin In many organisms, telophase I reveals a nuclear membrane forming around the dyads In this case, the nucleus next enters into a short interphase period If interphase occurs, the chromosomes not replicate because they already consist of two chromatids In other organisms, the cells go directly from anaphase I to meiosis II In general, meiotic telophase is much shorter than the corresponding stage in mitosis The Second Meiotic Division A second division, referred to as meiosis II, is essential if each gamete or spore is to receive only one chromatid from each original tetrad The stages characterizing meiosis II are shown on the right side of Figure 2–11 During prophase II, each dyad is composed of one pair of sister chromatids attached by the common centromeric region During metaphase II, the centromeres are positioned 14/08/15 3:01 PM www.downloadslide.com 64 Mito sis an d Meio sis Metaphase I Anaphase I Telophase I Prophase II F i g u r e – 11  The major events in meiosis in an animal cell with a diploid number of 4, beginning with metaphase I Note that the combination of chromosomes in the cells following telophase II is dependent on the random orientation of each tetrad and dyad when they align on the equatorial plate during metaphase I and metaphase II Several other combinations, which are not shown, can also be produced The events depicted here are described in the text 2–2 An organism has a diploid number of 16 in a primary oocyte (a) How many tetrads are present in the first meiotic prophase? (b) How many dyads are present in the second meiotic prophase? (c) How many monads migrate to each pole during the second meiotic anaphase? Hint: This problem involves an understanding of what happens to the maternal and paternal members of each pair of homologous chromosomes during meiosis, asking you to apply your understanding of chromosome behavior in an organism with a diploid number of 16 The key to its solution is your awareness that maternal and paternal homologs synapse during meiosis Once each chromatid has duplicated, creating a tetrad in the early phases of meiosis, each original pair behaves as a unit and leads to two dyads during anaphase I For more practice, see Problems 33, 34, and 35 M02_KLUG7260_11_GE_C02.indd 64 on the equatorial plate When the shugoshin complex is degraded, the centromeres separate, anaphase II is initiated, and the sister chromatids of each dyad are pulled to opposite poles Because the number of dyads is equal to the haploid number, telophase II reveals one member of each pair of homologous chromosomes present at each pole Each chromosome is now a monad Following cytokinesis in telophase II, four haploid gametes may result from a single meiotic event At the conclusion of meiosis II, not only has the haploid state been achieved, but if crossing over has occurred, each monad contains a combination of maternal and paternal genetic information As a result, the offspring produced by any gamete will receive a mixture of genetic information originally present in his or her grandparents Meiosis thus significantly increases the level of genetic variation in each ensuing generation 14/08/15 3:01 PM www.downloadslide.com 2.5 Metaphase II F i g u RE – 11 The Deve lopme nt o f G ame te s Va rie s in S pe rmatog e nesis C ompare d to Oo g en esis Anaphase II Haploid gametes   (Continued) 2.5 The Development of Gametes Varies in Spermatogenesis Compared to Oogenesis Although events that occur during the meiotic divisions are similar in all cells participating in gametogenesis in most animal species, there are certain differences between the production of a male gamete (spermatogenesis) and a female gamete (oogenesis) Figure 2–12 summarizes these processes Spermatogenesis takes place in the testes, the male reproductive organs The process begins with the enlargement of an undifferentiated diploid germ cell called a M02_KLUG7260_11_GE_C02.indd 65 Telophase II 65 spermatogonium This cell grows to become a primary spermatocyte, which undergoes the first meiotic division The products of this division, called secondary spermatocytes, contain a haploid number of dyads The secondary spermatocytes then undergo meiosis II, and each of these cells produces two haploid spermatids Spermatids go through a series of developmental changes, spermiogenesis, to become highly specialized, motile spermatozoa, or sperm All sperm cells produced during spermatogenesis contain the haploid number of chromosomes and equal amounts of cytoplasm Spermatogenesis may be continuous or may occur periodically in mature male animals; its onset is determined by the species’ reproductive cycles Animals that reproduce 14/08/15 3:01 PM www.downloadslide.com 66 Mito sis an d Meio sis Spermatogonium Oogonium Growth/Maturation Primary spermatocyte Primary oocyte Meiosis I Secondary spermatocytes Secondary oocyte First polar body Meiosis II Spermatids Ootid Second polar body Differentiation Ovum Spermatozoa F i g u re – 12   Spermatogenesis and oogenesis in animal cells year-round produce sperm continuously, whereas those whose breeding period is confined to a particular season produce sperm only during that time In animal oogenesis, the formation of ova (sing ovum), or eggs, occurs in the ovaries, the female reproductive organs The daughter cells resulting from the two M02_KLUG7260_11_GE_C02.indd 66 meiotic divisions of this process receive equal amounts of genetic material, but they not receive equal amounts of cytoplasm Instead, during each division, almost all the cytoplasm of the primary oocyte, itself derived from the oogonium, is concentrated in one of the two daughter cells The concentration of cytoplasm is necessary because a 14/08/15 3:01 PM www.downloadslide.com 2.7 Electron Mic roscopy Has Re ve ale d the Physica l S tru ctu re of Mitotic and Me iotic C h ro m o s o m es major function of the mature ovum is to nourish the developing embryo following fertilization During anaphase I in oogenesis, the tetrads of the primary oocyte separate, and the dyads move toward opposite poles During telophase I, the dyads at one pole are pinched off with very little surrounding cytoplasm to form the first polar body The first polar body may or may not divide again to produce two small haploid cells The other daughter cell produced by this first meiotic division contains most of the cytoplasm and is called the secondary oocyte The mature ovum will be produced from the secondary oocyte during the second meiotic division During this division, the cytoplasm of the secondary oocyte again divides unequally, producing an ootid and a second polar body The ootid then differentiates into the mature ovum Unlike the divisions of spermatogenesis, the two meiotic divisions of oogenesis may not be continuous In some animal species, the second division may directly follow the first In others, including humans, the first division of all oocytes begins in the embryonic ovary but arrests in prophase I Many years later, meiosis resumes in each oocyte just prior to its ovulation The second division is completed only after fertilization 2–3 Examine Figure 2–12, which shows oogenesis in animal cells Will the genotype of the second polar body (derived from meiosis II) always be identical to that of the ootid? Why or why not? Hint: This problem involves an understanding of meiosis during oogenesis, asking you to demonstrate your knowledge of polar bodies The key to its solution is to take into account that crossing over occurred between each pair of homologs during meiosis I 2.6 Meiosis Is Critical to Sexual Reproduction in All Diploid Organisms The process of meiosis is critical to the successful sexual reproduction of all diploid organisms It is the mechanism by which the diploid amount of genetic information is reduced to the haploid amount In animals, meiosis leads to the formation of gametes, whereas in plants haploid spores are produced, which in turn lead to the formation of haploid gametes Each diploid organism stores its genetic information in the form of homologous pairs of chromosomes Each pair consists of one member derived from the maternal parent and one from the paternal parent Following meiosis, M02_KLUG7260_11_GE_C02.indd 67 67 haploid cells potentially contain either the paternal or the maternal representative of every homologous pair of chromosomes However, the process of crossing over, which occurs in the first meiotic prophase, further reshuffles the alleles between the maternal and paternal members of each homologous pair, which then segregate and assort independently into gametes These events result in the great amount of genetic variation present in gametes It is important to touch briefly on the significant role that meiosis plays in the life cycles of fungi and plants In many fungi, the predominant stage of the life cycle consists of haploid vegetative cells They arise through meiosis and proliferate by mitotic cell division In multicellular plants, the life cycle alternates between the diploid sporophyte stage and the haploid gametophyte stage (Figure 2–13) While one or the other predominates in different plant groups during this “alternation of generations,” the processes of meiosis and fertilization constitute the “bridges” between the sporophyte and gametophyte stages Therefore, meiosis is an essential component of the life cycle of plants 2.7 Electron Microscopy Has Revealed the Physical Structure of Mitotic and Meiotic Chromosomes Thus far in this chapter, we have focused on mitotic and meiotic chromosomes, emphasizing their behavior during cell division and gamete formation An interesting question is why chromosomes are invisible during interphase but visible during the various stages of mitosis and meiosis Studies using electron microscopy clearly show why this is the case Recall that, during interphase, only dispersed chromatin fibers are present in the nucleus [Figure 2–14(a)] Once mitosis begins, however, the fibers coil and fold, condensing into typical mitotic chromosomes [Figure 2–14(b)] If the fibers comprising a mitotic chromosome are loosened, the areas of greatest spreading reveal individual fibers similar to those seen in interphase chromatin [Figure 2–14(c)] Very few fiber ends seem to be present, and in some cases, none can be seen Instead, individual fibers always seem to loop back into the interior Such fibers are obviously twisted and coiled around one another, forming the regular pattern of folding in the mitotic chromosome Starting in late telophase of mitosis and continuing during G1 of interphase, chromosomes unwind to form the long fibers characteristic of chromatin, which consist of DNA and associated proteins, particularly proteins called histones It is in this physical arrangement that DNA can most efficiently function during transcription and replication 14/08/15 3:01 PM www.downloadslide.com 68 Mito sis an d Meio sis Microsporangium (produces microspores) Zygote Megasporangium (produces megaspores) Sporophyte Diploid (2n) Fertilization Meiosis Haploid (n) Megaspore (n) Egg Female gametophyte (embryo sac) Sperm Microspore (n) Male gametophyte (pollen grain) F i g u r e – 13   Alternation of generations between the diploid sporophyte (2n) and the haploid gametophyte (n) in a multicellular plant The processes of meiosis and fertilization bridge the two phases of the life cycle In angiosperms (flowering plants), like the one shown here, the sporophyte stage is the predominant phase Electron microscopic observations of metaphase chromosomes in varying degrees of coiling led Ernest DuPraw to postulate the folded-fiber model, shown in Figure 2– 14(c) During metaphase, each chromosome consists of two sister chromatids joined at the centromeric region Each arm of the chromatid appears to be a single fiber wound much like a skein of yarn The fiber is composed of tightly coiled double-stranded DNA and protein An orderly coiling–twisting–condensing process appears to facilitate the transition of the interphase chromatin into the more condensed mitotic chromosomes Geneticists (a) (b) believe that during the transition from interphase to prophase, a 5000-fold compaction occurs in the length of DNA within the chromatin fiber! This process must be extremely precise given the highly ordered and consistent appearance of mitotic chromosomes in all eukaryotes Note particularly in the micrographs the clear distinction between the sister chromatids constituting each chromosome They are joined only by the common centromere that they share prior to anaphase We will return to this general topic later in the text when we consider chromosome structure in further detail (see Chapter 12) (c) F i g u r e – 14   Comparison of (a) the chromatin fibers characteristic of the interphase nucleus with (b) metaphase chromosomes that are derived from chromatin during mitosis Part (c) diagrams a mitotic chromosome, showing how chromatin is condensed to produce it Part (a) is a transmission electron micrograph and part (b) is a scanning electron micrograph M02_KLUG7260_11_GE_C02.indd 68 14/08/15 3:01 PM www.downloadslide.com S u mma ry P oi n t s 69 E x p l o r i n g G e n o mics P PubMed: Exploring and Retrieving Biomedical Literature ubMed is an Internet-based search system developed by the National Center of Biotechnology Information (NCBI) at the National Library of Medicine Using PubMed, one can access over 23 million articles in over 5600 biomedical journals The full text of many of the journals can be obtained electronically through college or university libraries, and some journals (such as Proceedings of the National Academy of Sciences USA; Genome Biology; and Science) provide free public access to articles within certain time frames In this exercise, we will explore PubMed to answer questions about relationships between tubulin, human cancers, and cancer therapies Exercise I – Tubulin, Cancer, and Mitosis C as e A Study In this chapter we were introduced to tubulin and the dynamic behavior of microtubules during the cell cycle Cancer cells are characterized by continuous and uncontrolled mitotic divisions Is it possible that tubulin and microtubules contribute to the development of cancer? Could these important structures be targets for cancer therapies? To begin your search for the answers, access the PubMed site at http:// www.ncbi.nlm.nih.gov/pubmed/ In the search box, type “tubulin cancer” and then click the “Search” button to perform the search To answer the question about tubulin’s association with cancer, you may want to limit your search to fewer papers, perhaps those that are review articles To this, click the “Review” link under the Article Types category on the left side of the page Explore some of the articles, as abstracts or as full text, available in your library or by free public access Prepare a brief report or verbally share your experiences with your class Describe two of the most important things you learned during your exploration and identify the information sources you encountered during the search Select several research papers and read the abstracts Timing is everything man in his early 20s received chemotherapy and radiotherapy as treatment every 60 days for Hodgkin’s disease After unsuccessful attempts to have children, he had his sperm examined at a fertility clinic, upon which multiple chromosomal irregularities were discovered When examined within days of a treatment, extra chromosomes were often present or one or more chromosomes were completely absent However, such irregularities were not observed at day 38 or thereafter Summary Points The structure of cells is elaborate and complex, with most com- ponents involved directly or indirectly with genetic processes In diploid organisms, chromosomes exist in homologous pairs, where each member is identical in size, centromere placement, and gene loci One member of each pair is derived from the maternal parent, and the other from the paternal parent M02_KLUG7260_11_GE_C02.indd 69 Visit the Study Area: Exploring Genomics How might a geneticist explain the time-related differences in chromosomal irregularities? Do you think that exposure to chemotherapy and radiotherapy of a spermatogonium would cause more problems than exposure to a secondary spermatocyte? What is the obvious advice that the man received regarding fertility while he remained under treatment? For activities, animations, and review quizzes, go to the Study Area Mitosis and meiosis are mechanisms by which cells distribute the genetic information contained in their chromosomes to progeny cells in a precise, orderly fashion Mitosis, which is but one part of the cell cycle, is subdivided into discrete stages that initially depict the condensation of chromatin into the diploid number of chromosomes Each chromosome first appears as a double structure, consisting of a 14/08/15 3:01 PM www.downloadslide.com 70 Mito sis an d Meio sis pair of identical sister chromatids joined at a common centromere As mitosis proceeds, centromeres split and sister chromatids are pulled apart by spindle fibers and directed toward opposite poles of the cell Cytoplasmic division then occurs, creating two new cells with the identical genetic information contained in the progenitor cell Meiosis converts a diploid cell into haploid gametes or spores, making sexual reproduction possible As a result of chromosome duplication, two subsequent meiotic divisions are required to achieve haploidy, whereby each haploid cell receives one member of each homologous pair of chromosomes There is a major difference between meiosis in males and in females Spermatogenesis partitions the cytoplasmic volume equally and produces four haploid sperm cells Oogenesis, on the other hand, collects the bulk of cytoplasm in one egg cell and reduces the other haploid products to polar bodies The extra cytoplasm in the egg contributes to zygote development following fertilization Meiosis results in extensive genetic variation by virtue of the exchange of chromosome segments during crossing over between maternal and paternal chromatids and by virtue of the random separation of maternal and paternal chromatids into gametes In addition, meiosis plays an important role in the life cycles of fungi and plants, serving as the bridge between alternating generations Mitotic chromosomes are produced as a result of the coiling and condensation of chromatin fibers of interphase into the characteristic form of chromatids I n sig h t s a n d S o l u t i o n s This appearance of “Insights and Solutions” begins a feature that will have great value to you as a student From this point on, “Insights and Solutions” precedes the “Problems and Discussion Questions” at each chapter’s end to provide sample problems and solutions that demonstrate approaches you will find useful in genetic analysis The insights you gain by working through the sample problems will improve your ability to solve the ensuing problems in each chapter In an organism with a diploid number of 2n = 6, how many individual chromosomal structures will align on the metaphase plate during (a) mitosis, (b) meiosis I, and (c) meiosis II? Describe each configuration (c) In meiosis II, the same number of structures exist (three), but in this case they are called dyads Each dyad is a pair of sister chromatids When crossing over has occurred, each chromatid may contain parts of one of its nonsister chromatids, obtained during exchange in prophase I Disregarding crossing over, draw all possible alignment configurations that can occur during metaphase for the chromosomes shown in Figure 2–11 Solution: As shown in the diagram below, four configurations are possible when n = Case I Case II Case III Case IV Solution for #2 Solution: (a) Remember that in mitosis, homologous chromosomes not synapse, so there will be six double structures, each consisting of a pair of sister chromatids In other words, the number of structures is equivalent to the diploid number (b) In meiosis I, the homologs have synapsed, reducing the number of structures to three Each is called a tetrad and consists of two pairs of sister chromatids M02_KLUG7260_11_GE_C02.indd 70 For the chromosomes in the previous problem, assume that each of the larger chromosomes has a different allele for a given gene, A OR a, as shown Also assume that each of the smaller chromosomes has a different allele for a second gene, B OR b Calculate the probability of generating each possible combination of these alleles (AB, Ab, aB, ab) following meiosis I 14/08/15 3:01 PM www.downloadslide.com 71 proble ms and d iscussio n qu es t i o ns Solution: As shown in the accompanying diagram: Case I AB and ab Case II Ab and aB Case III aB and Ab Case IV ab and AB Case I Case II A a A a B b b B Case III Case IV a A a A B b b B Solution for #3 Total: AB = 1p = 1/4 Ab = 1p = 1/4 aB = 1p = 1/4 How many different chromosome configurations can occur following meiosis I if three different pairs of chromosomes are present 1n = ? Solution: If n = 3, then eight different configurations would be possible The formula 2n, where n equals the haploid number, represents the number of potential alignment patterns As we will see in the next chapter, these patterns are produced according to the Mendelian postulate of segregation, and they serve as the physical basis of another Mendelian postulate called independent assortment Describe the composition of a meiotic tetrad during prophase I, assuming no crossover event has occurred What impact would a single crossover event have on this structure? Solution: Such a tetrad contains four chromatids, existing as two pairs Members of each pair are sister chromatids They are held together by a common centromere Members of one pair are maternally derived, whereas members of the other are paternally derived Maternal and paternal members are called nonsister chromatids A single crossover event has the effect of exchanging a portion of a maternal and a paternal chromatid, leading to a chiasma, where the two involved chromatids overlap physically in the tetrad The process of exchange is referred to as crossing over ab = 1p = 1/4 Problems and Discussion Questions How Do We Know ? In this chapter, we focused on how chromosomes are distributed during cell division, both in dividing somatic cells (mitosis) and in gamete- and spore-forming cells (meiosis) We found many opportunities to consider the methods and reasoning by which much of this information was acquired From the explanations given in the chapter, answer the following questions (a)  How we know that chromosomes exist in homologous pairs? (b)  How we know that DNA replication occurs during interphase, not early in mitosis? (c)  How we know that mitotic chromosomes are derived from chromatin? Concept Question Review the Chapter Concepts list on page 50 All of these pertain to conceptual issues involving mitosis or meiosis Based on these concepts, write a short essay that contrasts mitosis and meiosis, including their respective roles in organisms, the mechanisms by which they achieve their respective outcomes, and the consequences should either process fail to be executed with absolute fidelity M02_KLUG7260_11_GE_C02.indd 71 Visit for instructor-assigned tutorials and problems What role the following cellular components play in the storage, expression, or transmission of genetic information: (a) chromatin, (b) nucleolus, (c) ribosome, (d) mitochondrion, (e) centriole, (f) centromere? Discuss the concepts of homologous chromosomes, diploidy, and haploidy What characteristics two homologous chromosomes share? If two chromosomes of a species are the same length and have similar centromere placements and yet are not homologous, what is different about them? Describe the events that characterize each stage of mitosis How spindle fibers form and how chromosomes separate in animal cells? Compare chromosomal separation in plant and animal cells Why might different cells of the same organism have cell cycles of different durations? 10 Define and discuss these terms: (a) synapsis, (b) bivalents, (c) chiasmata, (d) crossing over, (e) chromomeres, (f ) sister chromatids, (g) tetrads, (h) dyads, (i) monads 11 Contrast the genetic content and the origin of sister versus nonsister chromatids during their earliest appearance in 14/08/15 3:01 PM www.downloadslide.com 72 Mito sis an d Meio sis prophase I of meiosis How might the genetic content of these change by the time tetrads have aligned at the equatorial plate during metaphase I? 12 Given the end results of the two types of division, why is it necessary for homologs to pair during meiosis and not desirable for them to pair during mitosis? 13 With increasing maternal age, the chances of observing trisomies increase significantly Increasing paternal age is associated with de novo point mutations Why? 14 How the stages of mitosis and meiosis occur in a specific order and never alternate? 15 Trisomy 21 or Down syndrome occurs when there is a normal diploid chromosomal complement of 46 chromosomes plus one (extra) chromosome #21 Such individuals therefore have 47 chromosomes Assume that a mating occurs between a female with Down syndrome and a normal 46-chromosome male What proportion of the offspring would be expected to have Down syndrome? Justify your answer 16 Considering the preceding problem, predict the number of different haploid cells that could be produced by meiosis if a fourth chromosome pair (W1 and W2) were added 17 During oogenesis in an animal species with a haploid number of 6, one dyad undergoes nondisjunction during meiosis II Following the second meiotic division, this dyad ends up intact in the ovum How many chromosomes are present in (a) the mature ovum and (b) the second polar body? (c) Following fertilization by a normal sperm, what chromosome condition is created? Extra-Spicy Problems As part of the “Problems and Discussion Questions” section in this and each subsequent chapter, we shall present a number of “ExtraSpicy” genetics problems We have chosen to set these apart in order to identify problems that are particularly challenging You may be asked to examine and assess actual data, to design genetics experiments, or to engage in cooperative learning Like genetic varieties of peppers, some of these experiences are just spicy and some are very hot We hope that you will enjoy the challenges that they pose For Problems 26–31, consider a diploid cell that contains three pairs of chromosomes designated AA, BB, and CC Each pair contains a maternal and a paternal member (e.g., Am and Ap) Using these designations, demonstrate your understanding of mitosis and meiosis by drawing chromatid combinations as requested Be sure to indicate when chromatids are paired as a result of replication and/or synapsis You may wish to use a large piece of brown manila wrapping paper or a cut-up paper grocery bag for this project and to work in partnership with another student We recommend cooperative learning as an efficacious way to develop the skills you will need for solving the problems presented throughout this text 26 In mitosis, what chromatid combination(s) will be present during metaphase? What combination(s) will be present at each pole at the completion of anaphase? 27 During meiosis I, assuming no crossing over, what chromatid combination(s) will be present at the completion of prophase? Draw all possible alignments of chromatids as migration begins during early anaphase M02_KLUG7260_11_GE_C02.indd 72 18 What is the probability that, in an organism with a haploid number of 10, a sperm will be formed that contains all 10 chromosomes whose centromeres were derived from maternal homologs? 19 During the first meiotic prophase, (a) when does crossing over occur; (b) when does synapsis occur; (c) during which stage are the chromosomes least condensed; and (d) when are chiasmata first visible? 20 Describe the role of meiosis in the life cycle of a vascular plant 21 How many sister chromatids are seen in the metaphase for a single chromosome? How different are these structures from the interphase chromatin? 22 What is the significance of checkpoints in the cell cycle? 23 You are given a metaphase chromosome preparation (a slide) from an unknown organism that contains 12 chromosomes Two that are clearly smaller than the rest appear identical in length and centromere placement Describe all that you can about these chromosomes 24 If one follows 50 primary oocytes in an animal through their various stages of oogenesis, how many secondary oocytes would be formed? How many first polar bodies would be formed? How many ootids would be formed? If one follows 50 primary spermatocytes in an animal through their various stages of spermatogenesis, how many secondary spermatocytes would be formed? How many spermatids would be formed? 25 Cell division cycle mutations render the mutants unable to continue the cell cycle This phenotype creates a paradox where mutant cells must also be grown in the lab to further identify the gene and study the role of the protein How you think this problem can be solved? Visit for instructor-assigned tutorials and problems 28 Are there any possible combinations present during prophase of meiosis II other than those that you drew in Problem 27? If so, draw them 29 Draw all possible combinations of chromatids during the early phases of anaphase in meiosis II 30 Assume that during meiosis I none of the C chromosomes disjoin at metaphase, but they separate into dyads (instead of monads) during meiosis II How would this change the alignments that you constructed during the anaphase stages in meiosis I and II? Draw them 31 Assume that each gamete resulting from Problem 30 fuses, in fertilization, with a normal haploid gamete What combinations will result? What percentage of zygotes will be diploid, containing one paternal and one maternal member of each chromosome pair? 32 A species of cereal rye (Secale cereale) has a chromosome number of 14, while a species of Canadian wild rye (Elymus canadensis) has a chromosome number of 28 Sterile hybrids can be produced by crossing Secale with Elymus (a)  What would be the expected chromosome number in the somatic cells of the hybrids? (b)  Given that none of the chromosomes pair at meiosis I in the sterile hybrid (Hang and Franckowlak, 1984), speculate on the anaphase I separation patterns of these chromosomes 33 An interesting procedure has been applied for assessing the chromosomal balance of potential secondary oocytes for use in human in vitro fertilization Using fluorescence in situ hybridization (FISH), Kuliev and Verlinsky (2004) were able 14/08/15 3:01 PM www.downloadslide.com E xtra -S pic y p ro bl ems to identify individual chromosomes in first polar bodies and thereby infer the chromosomal makeup of “sister” oocytes Assume that when examining a first polar body you saw that it had one copy (dyad) of each chromosome but two dyads of chromosome 21 What would you expect to be the chromosomal 21 complement in the secondary oocyte? What consequences are likely in the resulting zygote, if the secondary oocyte was fertilized? 34 Assume that you were examining a first polar body and noted that it had one copy (dyad) of each chromosome except chromosome 21 Chromosome 21 was completely absent What would you expect to be the chromosome 21 complement (only M02_KLUG7260_11_GE_C02.indd 73 73 with respect to chromosome 21) in the secondary oocyte? What consequences are likely in the resulting zygote if the secondary oocyte was fertilized? 35 Kuliev and Verlinsky (2004) state that there was a relatively high number of separation errors at meiosis I In these cases the centromere underwent a premature division, occurring at meiosis I rather than meiosis II Regarding chromosome 21, what would you expect to be the chromosome 21 complement in the secondary oocyte in which you saw a single chromatid (monad) for chromosome 21 in the first polar body? If this secondary oocyte was involved in fertilization, what would be the expected consequences? 14/08/15 3:01 PM www.downloadslide.com Gregor Johann Mendel, who in 1866 put forward the major postulates of transmission genetics as a result of experiments with the garden pea Mendelian Genetics Chapter Concepts ■ Inheritance is governed by information stored in discrete factors called genes ■ Genes are transmitted from generation to generation on vehicles called chromosomes ■ Chromosomes, which exist in pairs in diploid organisms, provide the basis of biparental inheritance ■ During gamete formation, chromosomes are distributed according to postulates first described by Gregor Mendel, based on his nineteenth-century research with the garden pea ■ Mendelian postulates prescribe that homologous chromosomes segregate from one another and assort independently with other segregating homologs during gamete formation ■ Genetic ratios, expressed as probabilities, are subject to chance deviation and may be evaluated statistically ■ The analysis of pedigrees allows predictions concerning the genetic nature of human traits A lthough inheritance of biological traits has been recognized for thousands of years, the first significant insights into how it takes place only occurred about 150 years ago In 1866, Gregor Johann Mendel published the results of a series of experiments that would lay the foundation for the formal discipline of genetics Mendel’s work went largely unnoticed until the turn of the twentieth century, but eventually, the concept of the gene as a distinct hereditary unit was established Since then, the ways in which genes, as segments of chromosomes, are transmitted to offspring and control traits have been clarified Research continued unabated throughout the twentieth century and into the present—indeed, studies in genetics, most recently at the molecular level, have remained at the forefront of biological research since the early 1900s When Mendel began his studies of inheritance using Pisum sativum, the garden pea, chromosomes and the role and mechanism of meiosis were totally unknown Nevertheless, he determined that discrete units of inheritance exist and predicted their behavior in the formation of gametes Subsequent investigators, with access to cytological data, were able to relate their own observations of chromosome behavior during meiosis and Mendel’s principles of inheritance Once this correlation was recognized, Mendel’s postulates were accepted as the basis for the study of what is known as transmission genetics—how genes are transmitted from parents to offspring These principles were derived directly from Mendel’s experimentation 74 M03_KLUG7260_11_GE_C03.indd 74 02/09/15 9:56 AM ... Genes    484 Segmentation Genes in Mice and Humans    485 A 01_ KLUG7260 _11 _GE_FM.indd 21 13 19 14 20 15 10 11 12 16 17 18 21 22 x 27/08 /15 4:02 PM www.downloadslide.com 22 CON TEN T S Cancer as... Polymerases    310 Replication through Chromatin    310 11 .7 The Ends of Linear Chromosomes Are Problematic during Replication  311 Telomere Structure    311 Replication at the Telomere    311 11 .8 DNA... Combinations of Two Gene Pairs with Two Modes of Inheritance Modify the 9:3:3 :1 Ratio  11 2 Evolving Concept of a Gene  11 2 4.8 Phenotypes Are Often Affected by More Than One Gene  11 3 Epistasis    11 4