genetics principles and analysis - daniel l. hartl

Retinoblastoma and Tumor-Suppressor Genes 298Chapter End Material Special Features Connection: The First Human Chromosomal Disorder Jerome Lejeune, Marthe Gautier, and Raymond Turpin 195

Page ii

TO THE BEST TEACHERS WE EVER HAD—OUR PARENTS AND OUR STUDENTS

ABOUT THE AUTHORS

Daniel L Hartl is a Professor of Biology at Harvard University He received his B.S degree and

Ph.D from the University of Wisconsin His research interests include molecular genetics,

molecular evolution, and population genetics Elizabeth W Jones is a Professor of Biological

Sciences at Carnegie Mellon University She received her B.S degree and Ph.D from the

University of Washington in Seattle Her research interests include gene regulation and the genetic control of cellular form Currently she is studying the function and assembly of organelles in the

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03 02 01 00 99 98 9 8 7 6 5 4 3 2

Pleiotropy: One Gene Can Affect More Than One Trait 17

Epistasis: One Trait Can Be Affected by More Than One Gene 19

Chapter End Material

Special Features

Connection: It's the DNA!

Oswald T Avery, Colin M MacLeod,

and Maclyn McCarty 1944

Studies on the chemical nature of the substance inducing

transformation of pneumococcal types

4

Connection: Shear Madness

Alfred D Hershey and Martha Chase 1952

Independent functions of viral protein and nucleic acid in

Mendel's Genetic Hypothesis and Its Experimental Tests 36

Verification of Mendelian Segregation by the Testcross 41

The Principle of Independent Assortment 42

Amorphs, Hypomorphs, and Other Types of Mutations 66

Chapter End Material

Analysis and Applications 76

Connection: This Land Is Your Land, This Land Is My Land

The Huntington's Disease Collaborative Research Group 1993

A novel gene containing a trinucleotide repeat that is expanded

and unstable on Huntington's disease chromosome

53

Nondisjunction As Proof of the Chromosome Theory of Heredity 103

3-5 Probability in Prediction and Analysis of Genetic Data 106

Evaluating the Fit of Observed Results to Theoretical Expectations 109

Chapter End Material

Analysis and Applications 119

Connection: The White-Eyed Male

Thomas Hunt Morgan 1910

Sex limited inheritance in Drosophila

101

Connection: The Case Against Mendel's Gardener

Ronald Aylmer Fisher 1936

Has Mendel's work been rediscovered?

Crossing-over Takes Place at the Four-Strand Stage of Meiosis 134

4-4 Genetic Mapping in Human Pedigrees 146

Chapter End Material

The linear arrangement of six sex-linked factors in Drosophila,

as shown by their mode of association

Page vi

Chapter 5

The Molecular Structure and Replication of the Genetic Material

172

5-3 What a Genetic Material Needs That DNA Supplies 181

The Basic Rule for the Replication of Nucleic Acids 182

5-7 The Isolation and Characterization of Particular DNA Fragments 199

Restriction Enzymes and Site-Specific DNA Cleavage 202

The Sequencing Procedure 212

Chapter End Material

Special Features

Connection: The Double Helix

James D Watson and Francis H C Crick 1953

A structure for deoxyribose nucleic acid

180

Connection: Replication by Halves

Matthew Meselson and Franklin W Stahl 1958

The replication of DNA in Escherichia coli

The Nucleosome Is the Basic Structural Unit of Chromatin 228

Nucleosome Core Particles 229

The Arrangement of Chromatin Fibers in a Chromosome 230

6-6 Repetitive Nucleotide Sequences in Eukaryotic Genomes 235

Analysis of Genome Size and Repetitive Sequences by

Chapter End Material

Connection: Telomeres: The Beginning of the End

Carol W Greider and Elizabeth H Blackburn 1987

The telomere terminal transferase of Tetrahymena is a

ribonucleoprotein enzyme with two kinds of primer specificity

249

Chromosome Abnormalities in Spontaneous Abortion 280

Retinoblastoma and Tumor-Suppressor Genes 298

Chapter End Material

Special Features

Connection: The First Human Chromosomal Disorder

Jerome Lejeune, Marthe Gautier, and Raymond Turpin 1959

Study of the somatic chromosomes of nine Down syndrome

Time-of-Entry Mapping 319

Genetic Recombination in Virulent Bacteriophages 331

Fine Structure of the rII Gene in Bacteriophage T4 336

8-7 Genetic Recombination in Temperate Bacteriophages 340

Chapter End Material

Special Features

Connection: The Sex Life of Bacteria

Joshua Lederberg and Edward L Tatum 1946

322

Gene recombination in Escherichia coli

Connection: Is a Bacteriophage an "Organism"?

Alfred D Hershey and Raquel Rotman 1948

Genetic recombination between host-range and plaque-type

mutants of bacteriophage in single bacterial cells

Page viii

Chapter 9

Genetic Engineering and Genome Analysis

358

Insertion of a Particular DNA Molecule into a Vector 366

The Use of Reverse Transcriptase: cDNA and RT-PCR 369

Production of Useful Proteins 386

Chapter End Material

Special Features

Connection: Hello, Dolly!

Ian Wilmut, Anagelika E Schnieke, Jim McWhir, Alex J Kind,

and Keith H S Campbell 1997

Viable offspring derived from fetal and adult mammalian cells

380

Connection: YAC-ity YAC

David T Burke, Georges F Carle and Maynard V Olson 1987

Cloning of large segments of exogenous DNA into yeast by

means of artificial chromosome vectors

What Are the Minimal Genetic Functions Needed for Life? 416

Chapter End Material

Chapter Summary 452

Page ix

Transfer RNA and Aminoacyl-tRNA Synthetase Enzymes 444

Special Features

Connection: One Gene, One Enzyme

George W Beadle and Edward L Tatum 1941

Genetic control of biochemical reactions in Neurospora

420

Connection: Messenger Light

Sydney Brenner, François Jacob and Matthew Meselson 1961

An unstable intermediate carrying information from genes to

ribosomes nature of the genetic code for proteind

439

Connection: Uncles and AuntsFrancis H C Crick, Leslie

Barnett, Sydney Brenner, and R J Watts-Tobin, 1961

General nature of the genetic code for proteins

11-2 Lactose Metabolism and the Operon 462

Inducible and Constitutive Synthesis and Repression 463

Transcriptional Activator Proteins 491

Chapter End Material

Special Features

Connection: Operator? Operator?

François Jacob, David Perrin, Carmen Sanchez, and Jacques

Monod 1960

The operon: A group of genes whose expression is coordinated

by an operator

467

Connection: Sex-Change Operations

James B Hicks, Jeffrey N Strathern, and Ira Herskowitz 1977

The cassette model of mating-type interconversion

484

GeNETics on the Web 506

Page x

Chapter 12

The Genetic Control of Development

510

Autonomous Development and Intercellular Signaling 514

Early Development and Activation of the Zygote Genome 518

Genetic Basis of Pattern Formation in Early Development 532

12-5 Genetic Control of Development in Higher Plants 543

Combinatorial Determination of the Floral Organs 545

Chapter End Material

Special Features

Connection: Distinguished Lineages

John E Sulston, E Schierenberg, J G White, and J N

Thomson 1983

The embryonic cell lineage of the nematode Caenorhabditis

elegans

521

Connection: Embryo Genesis

Christiane Nüsslein-Volhard and Eric Wieschaus 1980

Mutations affecting segment number and polarity in

13-3 Spontaneous Mutations 561

Genetic Effects of the Chernobyl Nuclear Accident 575

Asymmetrical Single-Strand Break Model 590

Chapter End Material

Connection: Replication Slippage in Unstable Repeats

Micheline Strand, Tomas A Prolla, R Michael Liskay, and

Thomas D Petes 1993

Destabilization of tracts of simple repetitive DNA in yeast by

mutations affecting DNA mismatch repair

579

Page xi

Chapter 14

Extranuclear Inheritance

598

Chapter End Material

Analysis and Applications 623

Special Features

Connection: Chlamydomonas Moment

Ruth Sager and Zenta Ramanis 1965

Recombination of nonchromosomal genes in Chlamydomonas

608

Connection: A Coming Together

Lynn Margulis (formerly Lynn Sagan) 1967

The origin of mitosing cells

DNA Exclusions 644

Calculation of the Inbreeding Coefficient from Pedigrees 647

Chapter End Material

Analysis and Applications 664

Connection: Be Ye Son or Nephew?

Alec J Jeffreys, John F Y Brookfield, and Robert Semeonoff

The Number of Genes Affecting a Quantitative Trait 681

Phenotypic Change with Selection: A Prediction Equation 684

16-6 Heritabilities of Threshold Traits 690

Chapter End Material

Connection: Human Gene Map

Jeffrey C Murry and 26 other investigators 1994

A comprehensive human linkage map with centimorgan density

17-2 Animal Behavior 714

The Mammalian Clock, Prion Protein, and Mad Cow Disease 723

Chapter End Material

Joan Fisher Box 1978

R A Fisher: The Life of a Scientist

Page xiii

Papers Excerpted in Connections in Chronological Order

Gregor Mendel 1866

Monastery of St Thomas,

Brno, Czech Republic

Experiments on Plant Hybrids

Verhandlungen des naturforschenden

Thomas Hunt Morgan 1910

Columbia University,New York,

The Mendelian Ratio in Relation

to Certain Orthopteran Chromosomes

Journal of Morphology 24: 487–511

Thomas Hunt Morgan 1913

Columbia University,

New York, New York

Heredity and Sex

Columbia University Press, New York

Alfred H Sturtevant 1913

Columbia University,

New York, New York

The Linear Arrangement of Six Sex-Linked

Factors in Drosophila, as Shown by Their

New York, New York

Non-crisscross Inheritance in Drosophila

Proceedings of the National

Academy of Sciences USA 27: 499–506

Oswald T Avery, Colin M.

MacLeod, and Maclyn McCarty

1944

The Rockefeller University,

New York, New York

Studies on the Chemical Nature of the Substance Inducing Transformation

New Haven, Connecticut

Gene Recombination in Escherichia

Host-Genetics 34: 44–71

Barbara McClintock 1950

Cold Spring Harbor Laboratory,

Cold Spring Harbor, New York

The Origin and Behavior of Mutable Loci in Maize

Proceedings of the National Academy

of Sciences USA 36: 344–355

Alfred D Hershey and Martha

Chase 1952

Cold Spring Harbor Laboratories,

Cold Spring Harbor, New York

Independent Functions of Viral Protein and Nucleic Acid in Growth of

West Lafayette, Indiana

Fine Structure of a Genetic Region in Bacteriophage

Proceedings of the National

Academy of Sciences USA

Proceedings of the National

Academy of Sciences of the USA

44:671–682

Jerome Lejeune, Marthe Gautier, and Raymond Turpin 1959

National Center for Scientific

Research, Paris, France

Study of the Somatic Chromosomes of Nine Down Syndrome Children

(original in French)

Comptes rendus des séances de

l'Académie des Sciences

de 248:1721–1722

François Jacob, David Perrin,

Carmen Sanchez and Jaques

Monod 1960

Institute Pasteur, Paris, France

The Operon: A Group of Genes Whose Expression Is Coordinated by an Operator (original in French)

Comptes Rendus des Séances de

l'Academie des Sciences

250:1727–1729

Sydney Brenner 1 , François

Jacob 2 and Matthew Meselson 3

1961

1Cavendish Laboratory,

Cambridge, England;

2Institute Pasteur, Paris, France;

3California Institute of Technology,Pasadena, California

An Unstable Intermediate Carrying

Information from Genes to Ribosomes for Protein Synthesis

Nature 190: 576–581

Page xiv

Francis H C Crick, Leslie

Barnett, Sydney Brenner, and

Gene Action in the X Chromosome

of the Mouse (Mus musculus L.)

Nature 190: 372

Ruth Sager and Zenta Ramanis

1965

Columbia University,

New York, New York

Recombination of Nonchromosomal Genes

The Origin of Mitosing Cells

Journal of Theoretical Biology

14:225–274

James B Hicks, Jeffrey N.

Strathern, and Ira Herskowitz

Pages 457–462 in Ahmad I Bukhari,

James A Shapiro, and Sankar L

Adhya (editors) DNA Insertion

Elements, Plasmids, and Episomes,

Cold Spring Harbor Laboratory,

Cold Spring Harbor, New York

Joan Fisher Box 1978

Madison, Wisconsin

R A Fisher: The Life of a Scientist

John Wiley & Sons, New York

Christiane Nüsslein-Volhard

and Eric Wieschaus 1980

European Molecular Biology

John E Sulston 1 , E Schierenberg 2 ,

J G White 1 , and J N Thomson 1

1983

1Medical Research Council

Laboratory for Molecular Biology,Cambridge, England;

2Max-Planck Institute for

Alec J Jeffreys, John F Y.

Brookfield, and Robert

Semeonoff 1985

University of Leicester,

Leicester, England

Positive Identification of an Immigration

Test-Case Using Human DNA

Specificity

Cell 51:887–898

Micheline Strand 1 , Tomas A.

Prolla 2 , R Michael Liskay 2 ,

and Thomas D Petes 1 1993

1University of North Carolina,

Chapel Hill, North Carolina

2Yale University,

New Haven, Connecticut

Destabilization of Tracts of Simple

Repetitive DNA in Yeast by Mutations Affecting DNA Mismatch Repair

Nature 365: 274–276

The Huntington's Disease

Collaborative Research Group 1993

Comprising 58 authors among

9 institutions

A Novel Gene Containing a Trinucleotide Repeat That is Expanded and Unstable on Huntington's Disease Chromosomes

Ian Wilmut, Anagelika E.

Schnieke, Jim McWhir, Alex J.

Kind, and Keith H S Campbell 1997

Roslin Institute, Roslin, Midlothian,Scotland

Viable Offspring Derived from Fetal and Adult Mammalian Cells

Nature 385: 810–813

Page xv

Preface

This book is titled Genetics: Principles and Analysis, Fourth Edition, because it embodies our belief

that a good course in genetics should maintain the right balance between two important aspects of the science The first aspect is that genetics is a body of knowledge pertaining to genetic

transmission, function, and mutation This constitutes the Principles The second aspect is that

genetics is an experimental approach, or a kit of "tools," for the study of biological processes such

as development or behavior This is Analysis.

The overall aim of Genetics: Principles and Analysis, Fourth Edition, is to provide a clear,

comprehensive, rigorous, and balanced introduction to genetics at the college level It is a guide to learning a critically important and sometimes difficult subject The rationale of the book is that any student claiming a knowledge of genetics must:

• Understand the basic processes of gene transmission, mutation, expression, and regulation;

• Be able to think like a geneticist at the elementary level of being able to formulate genetic

hypotheses, work out their consequences, and test the results against observed data;

• Be able to solve problems of several types, including problems that ask the student to verbalize genetic principles in his or her own words, single-concept exercises that require application of definitions or the basic principles of genetics, genetic analysis in which several concepts must be applied in logical order, and quantitative problems that call for some numerical calculation;

• Gain some sense of the social and historical context in which genetics has developed and is

continuing to develop; and

• Have some familiarity with the genetic resources and information that are available through the Internet

Genetics: Principles and Analysis, Fourth Edition, incorporates many special features to help

students achieve these learning goals The text is clearly and concisely written in a somewhat

relaxed prose style without being chummy or excessively familiar Each chapter is headed by a list

of Principles that are related at numerous points to the larger whole Each chapter contains two or three Connections in which the text material is connected to excerpts of classic papers that report

key experiments in genetics or that raise important social, ethical, or legal issues in genetics Each Connection has a brief introduction of its own, explaining the importance of the experiment and the

historical context in which it was carried out At the end of each chapter is a complete Summary, Key Terms, GeNETics on the web exercises that guide students in the use of Internet resources in genetics, and several different types and levels of Problems These features are discussed

individually below

In recent decades, both the amount of genetic knowledge and its rate of growth have exploded Many of the new discoveries have personal and social relevance through applications of genetics to human affairs in prenatal diagnosis, testing for carriers, and identification of genetic risk factors for complex traits, such as breast cancer and heart disease There are also ethical controversies: Should genetic manipulation be used on patients for the treatment of disease? Should human fetuses be used

in research? Should human beings be cloned? There are also social controversies—for example, when insurance companies exclude coverage of people because of their inherited risks of certain diseases

Inspired in part by the controversies and the publicity, many of today's students come to a course in