Human genetics concepts and applications ricki lewis pdf

Human Genetics

Human Genetics Concepts and Applications

Ricki Lewis Genetic Counselor CareNet Medical Group Schenectady, New York

Adjunct Assistant Professor of Medical Education Alden March Bioethics Institute Albany Medical College

Writer, Medscape Medical News

Blogger, Public Library of Science

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HUMAN GENETICS: CONCEPTS AND APPLICATIONS, ELEVENTH EDITION

Published by McGraw-Hill Education, 2 Penn Plaza, New York, NY 10121. Copyright © 2015 by McGraw-Hill Education. All rights reserved. Printed in the United States of America. Previous editions © 2012, 2010, and 2008. No part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written consent of McGraw-Hill Education, including, but not limited to, in any network or other electronic storage or transmission, or broadcast for distance learning.

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Library of Congress Cataloging-in-Publication Data Lewis, Ricki. Human genetics : concepts and applications/Ricki Lewis, Genetic Counselor, CareNet Medical Group, Sche- nectady, New York, Adjunct Assistant Professor of medical education, Alden March Bioethics Institute, Albany Medical College, writer, Medscape Medical News, blogger, Public Library of Science.—Eleventh edition. pages cm ISBN 978-0-07-352536-5 (alk. paper) 1. Human genetics—Textbooks. I. Title. QH431.L41855 2015 599.93’5—dc23

2014020906

The Internet addresses listed in the text were accurate at the time of publication. The inclusion of a website does not indicate an endorsement by the authors or McGraw-Hill Education, and McGraw-Hill Education does not guarantee the accuracy of the information presented at these sites.

www.mhhe.com

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iii

About the Author Ricki Lewis has built an eclectic career in communicating the excitement of genetics

and genomics. She earned her Ph.D. in genetics in 1980 from Indiana University.

It was the dawn of the modern biotechnology era, which Ricki chronicled in many

magazines and journals. She published one of the first articles on DNA fingerprinting

in Discover magazine in 1988, and a decade later one of the first articles on human

stem cells in The Scientist.

Ricki has taught a variety of life science courses at Miami University, the University

at Albany, Empire State College, and community colleges. She has authored or

co-authored several university-level textbooks and is the author of The Forever Fix:

Gene Therapy and the Boy Who Saved It, as well as an essay collection and a novel .

Ricki has been a genetic counselor for a private medical practice since 1984 and is

a frequent public speaker. Since 2012, Ricki has written hundreds of news stories

for Medscape Medical News, articles for Scientific American and for several genetic

disease organizations, and originated and writes the popular weekly DNA Science

blog at Public Library of Science.

Ricki teaches an online course on “Genethics” for the Alden March Bioethics Institute

of Albany Medical College. She lives in upstate New York and sometimes Martha’s

Vineyard, with husband Larry and several felines. Contact Ricki at rickilewis54@gmail.

com , or join the discussion on DNA Science at http://blogs.plos.org/dnascience/ .

Dedicated to the

families who live with genetic diseases, the

health care providers who help them, and

the researchers who develop new tests

and treatments.

Dedicated to the

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iv

C H A P T E R 12 Gene Mutation 212

C H A P T E R 13 Chromosomes 237

P A R T 4 PP A Population Genetics 263

C H A P T E R 14 Constant Allele Frequencies 263

C H A P T E R 15 Changing Allele Frequencies 279

C H A P T E R 16 Human Ancestry and Evolution 302

P A R T 5 PP A Immunity and

Cancer 326 C H A P T E R 17 Genetics of Immunity 326

C H A P T E R 18 Cancer Genetics and Genomics 351

P A R T 6 P AAP Genetic Technology 374

C H A P T E R 19 Genetic Technologies: Patenting, Modifying, and Monitoring DNA 374

C H A P T E R 20 Genetic Testing and Treatment 389

C H A P T E R 21 Reproductive Technologies 407

C H A P T E R 22 Genomics 425

P A R T 1 PP A Introduction 1

C H A P T E R 1 What Is in a Human Genome? 1

C H A P T E R 2 Cells 15

C H A P T E R 3 Meiosis, Development, and Aging 42

P A R T 2 PP A Transmission

Genetics 68 C H A P T E R 4 Single-Gene Inheritance 68

C H A P T E R 5 Beyond Mendel’s Laws 89

C H A P T E R 6 Matters of Sex 110

C H A P T E R 7 Multifactorial Traits 130

C H A P T E R 8 Genetics of Behavior 148

P A R T 3 PP A DNA and

Chromosomes 163 C H A P T E R 9 DNA Structure and Replication 163

C H A P T E R 10 Gene Action: From DNA to Protein 180

C H A P T E R 11 Gene Expression and Epigenetics 199

Brief Contents

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v

Contents About the Author iii

Preface ix

Applying Human Genetics xiii

The Human Touch xiv

The Lewis Guided Learning System xv

P A R T 1 Introduction 1 C H A P T E R 1 CC HH

What Is in a Human Genome? 1 1.1 Introducing Genes and Genomes 2

1.2 Levels of Genetics and Genomics 3

1.3 Applications of Genetics and Genomics 7

1.4 A Global Perspective on Genomes 9

C H A P T E R 2 CC HHC Cells 15

2.1 Introducing Cells 16

2.2 Cell Components 16

2.3 Cell Division and Death 28

2.4 Stem Cells 33

2.5 The Human Microbiome 37

C H A P T E R 3 CC HH Meiosis, Development,

and Aging 42 3.1 The Reproductive System 43

3.2 Meiosis 44

3.3 Gametes Mature 47

3.4 Prenatal Development 51

3.5 Birth Defects 59

3.6 Maturation and Aging 62

P A R T 2 Transmission Genetics 68 C H A P T E R 4

CC HH

Single-Gene Inheritance 68 4.1 Following the Inheritance of One Gene 69

4.2 Single-Gene Inheritance Is Rare 72

4.3 Following the Inheritance of More Than One Gene 77

4.4 Pedigree Analysis 79

4.5 Family Exome Analysis 83

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vi Contents

C H A P T E R 5 CC HH Beyond Mendel’s

Laws 89 5.1 When Gene Expression Appears to Alter

Mendelian Ratios 90

5.2 Mitochondrial Genes 98

5.3 Linkage 100

C H A P T E R 6 CC HH1 21 2 1 2

3

3 4 5 6 7 8 9 10 11

4

I

II

III

IV

V

21 3 4 5

1 2 Matters of Sex 110 6.1 Our Sexual Selves 111

6.2 Traits Inherited on Sex Chromosomes 117

6.3 Sex-Limited and Sex-Influenced Traits 122

6.4 X Inactivation 122

6.5 Parent-of-Origin Effects 124

C H A P T E R 7 CC HH Multifactorial Traits 130

7.1 Genes and the Environment Mold Traits 131

7.2 Polygenic Traits Are Continuously Varying 133

7.3 Methods to Investigate Multifactorial Traits 135

7.4 A Closer Look: Body Weight 142

C H A P T E R 8 CC HH Genetics of Behavior 148

8.1 Genes and Behavior 149

8.2 Sleep 150

8.3 Intelligence and Intellectual Disability 151

8.4 Drug Addiction 152

8.5 Mood Disorders 154

8.6 Schizophrenia 155

8.7 Autism 157

P A R T 3 DNA and Chromosomes 163 C H A P T E R 9 CC HH

DNA Structure and Replication 163 9.1 Experiments Identify and Describe the

Genetic Material 164

9.2 DNA Structure 168

9.3 DNA Replication—Maintaining Genetic Information 170

9.4 Sequencing DNA 176

C H A P T E R 10 CC HH H

C C

CH2

CH2

CH2

H2N NH

NH

C

H O

OHH

mino oup

Ac gro

Arginine R

group

N

Gene Action: From DNA to Protein 180 10.1 Transcription Copies the Information in

DNA 181

10.2 Translation of a Protein 186

10.3 Processing a Protein 192

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Contents vii

12.4 Causes of Mutation 218

12.5 Types of Mutations 221

12.6 The Importance of Position 227

12.7 DNA Repair 229

C H A P T E R 13 CC HH Chromosomes 237

13.1 Portrait of a Chromosome 238

13.2 Detecting Chromosomes 240

13.3 Atypical Chromosome Number 244

13.4 Atypical Chromosome Structure 253

13.5 Uniparental Disomy—A Double Dose from One Parent 258

C H A P T E R 11 CC HH Gene Expression

and Epigenetics 199 11.1 Gene Expression Through Time

and Tissue 200

11.2 Control of Gene Expression 203

11.3 Maximizing Genetic Information 205

11.4 Most of the Human Genome Does Not Encode Protein 206

C H A P T E R 12 CC HH Gene Mutation 212

12.1 The Nature of Mutations 213

12.2 A Closer Look at Two Mutations 214

12.3 Allelic Disorders 217

P A R T 4 Population Genetics 263 C H A P T E R 14 CC HH

Constant Allele Frequencies 263 14.1 Population Genetics Underlies

Evolution 264

14.2 Constant Allele Frequencies 265

14.3 Applying Hardy-Weinberg Equilibrium 267

14.4 DNA Profiling Uses Hardy-Weinberg Assumptions 268

C H A P T E R 15 CC HH Changing Allele

Frequencies 279 15.1 Nonrandom Mating 280

15.2 Migration 281

15.3 Genetic Drift 282

15.4 Mutation 286

15.5 Natural Selection 287

15.6 Eugenics 295

C H A P T E R 16 CC HH Human Ancestry

and Evolution 302 16.1 Human Origins 303

16.2 Methods to Study Molecular Evolution 311

16.3 The Peopling of the Planet 314

16.4 What Makes Us Human? 318

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viii Contents

P A R T 5 Immunity and Cancer 326

P A R T 6 Genetic Technology 374

C H A P T E R 17 CC HH Genetics of

Immunity 326 17.1 The Importance of Cell Surfaces 327

17.2 The Human Immune System 330

17.3 Abnormal Immunity 335

17.4 Altering Immunity 341

17.5 Using Genomics to Fight Infection 345

C H A P T E R 19 C HHC Genetic Technologies:

Patenting, Modifying, and Monitoring DNA 374 19.1 Patenting DNA 375

19.2 Modifying DNA 376

19.3 Monitoring Gene Function 382

19.4 Gene Silencing and Genome Editing 384

C H A P T E R 20 CC HH Genetic Testing and

Treatment 389 20.1 Genetic Counseling 390

20.2 Genetic Testing 392

20.3 Treating Genetic Disease 397

C H A P T E R 18 CC HH Cancer Genetics

and Genomics 351 18.1 Cancer Is an Abnormal Growth That Invades

and Spreads 352

18.2 Cancer at the Cellular Level 356

18.3 Cancer Genes and Genomes 360

18.4 The Challenges of Diagnosing and Treating Cancer 369

C H A P T E R 21 CC HHCellMitochondriaMitochondrialDNA Mitochondrion

Mitochondrial DNA = 37 genes

Reproductive Technologies 407 21.1 Savior Siblings and More 408

21.2 Infertility and Subfertility 409

21.3 Assisted Reproductive Technologies 411

21.4 Extra Embryos 419

C H A P T E R 22 CC HH Genomics 425

22.1 From Genetics to Genomics 426

22.2 Analysis of the Human Genome 430

22.3 Personal Genome Sequencing 435

Glossary G-1 Credits C-1 Index I-1

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Typewritten Text
ix

Human Genetics Touches Us All

When I wrote the first edition of this book, in 1992, I could never have imagined that today, thousands of people would have had their genomes sequenced. Nor could I have imagined, when the first genomes were sequenced a decade later, that the process could take under a day, for less than $1,000. Of course, under- standing all the information in a human genome will take much longer.

Each subsequent edition opened with a scenario of two students taking genetic tests, which grew less hypothetical and more real over time, even reaching the direct-to-consumer level. This new edition reflects the translation of gene and genome testing and manipulation from the research lab to the clinic.

The eleventh edition opens with “ Eve’s Genome ” and ends with “ Do You Want Your Genome Sequenced? ” In between, the text touches on what exome and genome sequencing have revealed about single-gene diseases so rare that they affect only a sin- gle family, to clues to such common and complex condi- tions as intellectual disability and autism. Exome and genome sequencing are also important in such varied areas as understanding our origins, solving crimes, and tracking epidemics. In short, DNA sequencing will affect most of us.

As the cost of genome sequencing plummets, we all may be able to look to our genomes for echoes of our pasts and hints of our futures—if we so choose. We may also learn what we can do to counter our inherited tendencies and susceptibilities. Genetic knowledge is informative and empowering. This book shows you how and why this is true.

Ricki Lewis

Today, human genetics is for everyone. It is about our variation more than about our illnesses, and about the common as well as the rare. Once an obscure science or an explanation for an odd collection of symptoms, human genetics is now part of everyday conversation. At the same time, it is finally being recognized as the basis of medical science, and health care professionals must be fluent in the field’s language and concepts. Despite the popu- lar tendency to talk of “a gene for” this or that, we now know that for most traits and illnesses, several genes interact with each other and environmental influences to mold who we are.

What Sets This Book Apart Current Content The exciting narrative writing style, with clear explanations of concepts and mechanisms propelled by stories, reflects Dr. Lewis’s eclectic experience as a medical news writer, blog- ger, professor, and genetic counselor, along with her expertise in genetics. Updates to this edition include

■ Genetic tests, from preconception to old age ■ Disease-in-a-dish stem cell technology ■ From Mendel to molecules: family exome analysis ■ Allelic diseases: one gene, more than one disease ■ Admixture of archaic and modern humans ■ Gene silencing and genome editing ■ Cancer genomes guide treatment ■ The reemergence of gene therapy ■ Personal genome sequencing: promises and limitations

The transition of genetics to genomics catalyzed slight reorga- nization of the book. The order of topics remains, but material that had been boxed or discussed in later chapters because it was once new technology has been moved up as the “applica- tions” become more integrated with the “concepts.” The book has evolved with the science.

The Human Touch Human genetics is about people, and their voices echo through- out these pages. They speak in the narrative as well as in many new chapter introductions, boxes, stories, and end-of-chapter questions and cases.

Compelling Stories and Cases When the parents of children with visual loss stood up at a conference to meet other families with the same very rare inherited disease, Dr. Lewis was there, already composing the opening essay to chapter 5. She knows the little girl in the “ In Their Own Words ” essay in chapter 2 and on the cover with her dog, who is 1 of about 70 people in the world with giant axonal neuropathy. Perhaps there is no more heart-wrenching image of Mendelian inheritance than the chapter 4 opening photo of a daughter and father, who died from Huntington disease within weeks of each other.

Clinical Application of Human Genetics A working knowl- edge of the principles and applications of human genetics is critical to being an informed citizen and health care consumer. Broad topics of particular interest include

■ The roles that genes play in disease risk, physical characteristics, and behavior, with an eye toward the dangers of genetic determinism

Preface

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■ Biotechnologies, including next-generation DNA sequencing, genetic testing, stem cell technology, archaic human genome sequencing, gene therapy, familial DNA searches, exome sequencing, cell-free fetal DNA testing, and personal genome sequencing

■ Ethical concerns that arise from the interface of genetic and genomic information and privacy.

The Lewis Guided Learning System Each chapter begins with two views of the content. “ Learning Outcomes ” embedded in the table of contents guide the stu- dent in mastering material. “ The Big Picture ” encapsulates the overall theme of the chapter. The chapter opening essay and figure grab attention. Content flows logically through three to

five major sections per chapter that are peppered with high- interest boxed readings (“ In Their Own Words, ” “ Clinical Con- nections, ” “ Bioethics: Choices for the Future, ” “A Glimpse of History,” and “ Technology Timelines” ). End-of-chapter peda- gogy progresses from straight recall to applied and creative questions and challenges.

Dynamic Art Outstanding photographs and dimensional illustrations, vibrantly colored, are featured throughout Human Genetics: Concepts and Applications. Figure types include process figures with numbered steps, micro to macro representations, and the combination of art and photos to relate stylized draw- ings to real-life structures.

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New to This Edition!

The genomics of today evolved from the genetics of the twen- tieth century. A Glimpse of History features throughout the book capture key moments in time. Clinical Connections bring chapter concepts to patients and health care providers, with thought-provoking questions for discussion. Key Concepts after all major sections are now questions.

Highlights in the new edition include the following:

Chapter 1 What Is in a Human Genome? ■ The story of young Nicholas Volker, near death when

exome sequencing led to a diagnosis—and a treatment

Chapter 2 Cells ■ The human microbiome

Chapter 3 Meiosis, Development, and Aging ■ Progress for progeria ■ Maternal and paternal age effects on gametes

Chapter 4 Single-Gene Inheritance ■ Family exome analysis solves a medical mystery

Chapter 7 Multifactorial Traits ■ Blond hair among the Melanesians ■ Smoking-related lung cancer

Chapter 8 Genetics of Behavior ■ Genetic risks for posttraumatic stress disorder,

depression, autism ■ Heritability of intelligence at different ages

Chapter 11 Gene Expression and Epigenetics ■ Long noncoding RNAs

Chapter 12 Gene Mutation ■ Gonadal mosaicism ■ Allelic disease—more common than we thought ■ Exon skipping causes and treats disease

Chapter 13 Chromosomes ■ Harnessing XIST to silence trisomy 21 ■ Cell-free fetal DNA for noninvasive prenatal diagnosis

Chapter 15 Changing Allele Frequencies ■ The Clinic for Special Children treats the Amish

Chapter 16 Human Ancestry and Evolution ■ Updated terminology and evolutionary trees ■ Admixture, the Neanderthals, Denisovans, and us ■ What makes us human?

Chapter 17 Genetics of Immunity ■ Genomic epidemiology tracks an outbreak ■ Reverse vaccinology ■ Mimicking CCR5 mutations to prevent HIV infection

Chapter 18 Cancer Genetics and Genomics ■ Summary figure of cancer at different levels

■ Driver and passenger mutations ■ Cancer genomes ■ Cell-free tumor DNA ■ How BRCA1 causes cancer

Chapter 19 Genetic Technologies: Patenting, Modifying, and Monitoring DNA

■ The Supreme court and DNA patents ■ Gene silencing and genome editing

Chapter 22 Genomics ■ Genome sequencing and annotation ■ Practical medical matters ■ Types of information in human genomes ■ A gallery of genomes ■ Comparative genomics ■ Do you want your genome sequenced?

NEW FIGURES

4.6 Eye color 4.8 Loss-of-function and gain-of-function mutations 7.10 Copy number variants 8.6 Nicotine’s effects at the cellular level 8.9 Exome sequencing and autism 9.17 Replication bubbles 12.5 Allelic disease of connective tissue 12.10 Exon skipping and Duchenne muscular dystrophy 13.14 XIST silences trisomy 21 14.11 Several steps identify STRs 15.13 Antibiotic resistance 16.13 Admixture of haplotypes 16.18 What makes us human? 17.14 Filaggrin and allergy 17.18 Genome sequencing to track outbreaks 18.1 Levels of cancer 18.12 Evolution of a cancer 18.13 Cancer chromosomes 19.7 Gene silencing and genome editing

NEW TABLES

2.2 Stem Cell Sources 3.4 Longevity Genes 7.6 Study Designs for Multifactorial Traits 13.2 Maternal Serum Markers 15.1 Clinical Connection: Genetic Disorders among the Amish 19.2 Genetically Modified Foods 22.1 Selected Projects to Analyze Human Genomes 22.2 Cost of Sequencing Human Genomes 22.3 A Gallery of Genomes

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xii Preface

ACKNOWLEDGMENTS

Human Genetics: Concepts and Applications, Eleventh Edition, would not have been possible without the editorial and pro- duction dream team: senior brand manager Rebecca Olson, product development director Rose Koos, executive marketing manager Patrick Reidy, lead content licensing specialist Car- rie Burger, designer Tara McDermott, developmental editors Anne Winch, Erin Guendelsberger, and Emily Nesheim, proj- ect manager Sheila Frank, copyeditor Beatrice Sussman, and photo editor extraordinaire, Toni Michaels. Many thanks to the fabulous reviewers. Special thanks to my friends in the rare dis- ease community who have shared their stories, and to Jonathan Monkemeyer and David Bachinsky for helpful Facebook posts. As always, many thanks to my wonderful husband Larry for his support and encouragement and to my three daughters, my cats, and Cliff the hippo.

Eleventh Edition Reviewers Andy Andres

Boston University Elizabeth Alter

York College Ann Blakey

Ball State University Bruce Bowerman

University of Oregon James Bradshaw

Utah Valley University Dean Bratis

Villanova University Susan Brown

Kansas State University Michelle Coach

Asnuntuck Community College Jonathon S. Coren

Elizabethtown College Tracie Delgado

Northwest University

Dan Dixon University of Kansas Medical Center

Jennifer Drew University of Florida

Gregory Filatov University of California Riverside

Yvette Gardner Clayton State University

Ricki Glaser Stevenson University

Debra Han Palomar Community College

Bradley J. Isler Ferris State University

Bridget Joubert Northwestern State University

Patricia Matthews Grand Valley State University

Gemma Niermann University of California, Berkeley and Saint Mary’s College

Ruth S. Phillips North Carolina Central University

Mabel O. Royal North Carolina Central University

Mark Sanders University of California, Davis

Jennifer Smith Triton College

Michael Torres Warren Wilson College

Jo Ann Wilson Florida Gulf Coast University

Erin Zimmer Lewis University

This book continually evolves thanks to input from instructors and students. Please let me know your thoughts and sugges- tions for improvement. ( rickilewis54@gmail.com )

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xiii

Chapter Openers 1 Eve’s Genome 1

2 Diagnosis From a Tooth 15

3 Progress for Progeria 42

4 Juvenile Huntington Disease: The Cruel Mutation 68

5 Mutations in Different Genes Cause Blindness 89

6 Stem Cell and Gene Therapies Save Boys’ Lives 110

7 The Complex Genetics of Athletics 130

8 Genetic Predisposition to Posttraumatic Stress Disorder 148

9 On the Meaning of Gene 163

10 An Inborn Error of Arginine Production 180

11 The Dutch Hunger Winter 199

12 One Mutation, Multiple Effects: Osteogenesis Imperfecta 212

13 The Curious Chromosomes of Werewolves 237

14 Postconviction DNA Testing 263

15 The Evolution of Lactose Tolerance 279

16 The Little Lady of Flores 302

17 Mimicking a Mutation to Protect Against HIV 326

18 A Genetic Journey to a Blockbuster Cancer Drug 351

19 Improving Pig Manure 374

20 Fighting Canavan Disease 389

21 Replacing Mitochondria 407

22 100,000 Genomes and Counting 425

Applying Human Genetics

A GLIMPSE OF HISTORY Chapter 3 The first view of sperm Chapter 4 Gregor Mendel Chapter 5 The murdered Romanovs and mitochondrial DNA Chapter 9 Kary Mullis invents PCR Chapter 10 The RNA tie club Chapter 12 The discovery of sickled cells Chapter 13 Determining the human chromosome number Chapter 14 Famous forensics cases Chapter 15 Malaria in the United States Chapter 18 Retinoblastoma Chapter 20 Treating PKU Chapter 22 Comparative genomics

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xiv

Clinical Connections 1.1 Exome Sequencing Saves a Boy’s Life 10

2.1 Inborn Errors of Metabolism Affect the Major Biomolecules 19

2.2 Faulty Ion Channels Cause Inherited Disease 26

3.1 When an Arm Is Really a Leg: Homeotic Mutations 55

4.1 It’s All in the Genes 73

4.2 “65 Roses”: Progress in Treating Cystic Fibrosis 76

5.1 The Genetic Roots of Alzheimer Disease 96

6.1 Colorblindness 119

7.1 Many Genes Control Heart Health 132

12.1 Fragile X Mutations Affect Boys and Their Grandfathers 226

14.1 DNA Profiling: Molecular Genetics Meets Population Genetics 270

15.1 The Clinic for Special Children: The Founder Effect and “Plain” Populations 284

17.1 Viruses 328

17.2 A Special Immunological Relationship: Mother-to-Be and Fetus 339

18.1 The Story of Gleevec 364

21.1 The Case of the Round-Headed Sperm 410

In Their Own Words A Little Girl with Giant Axons 28

Growing Human Mini-Brains 58

The Y Wars 113

Familial Dysautonomia: Rebekah’s Story 223

Some Individuals With Trisomies Survive Childhood 251

Bioethics: Choices for the Future Genetic Testing and Privacy 11

Banking Stem Cells: When Is It Necessary? 37

Why a Clone Is Not an Exact Duplicate 52

Infidelity Testing 175

Will Trisomy 21 Down Syndrome Disappear? 250

Should DNA Collected Today Be Used to Solve a Past Crime? 275

Two Views of Neural Tube Defects 297

Genetic Privacy: A Compromised Genealogy Database 318

Pig Parts 345

EPO: Built-in Blood Cell Booster or Performance-Enhancing Drug? 379

Incidental Findings: Does Sequencing Provide Too Much Information? 395

Removing and Using Gametes After Death 416

The Human Touch

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Technology Timeline

P A T E N T I N G L I F E A N D G E N E S

1790 U.S. patent act enacted. A patented invention must be new, useful, and not obvious.

1873 Louis Pasteur is awarded first patent on a life form, for yeast used in industrial processes.

1930 New plant variants can be patented.

1980 First patent awarded on a genetically modified organism, a bacterium given four DNA rings that enable it to metabolize components of crude oil.

1988 First patent awarded for a transgenic organism, a mouse that manufactures human protein in its milk. Harvard University granted patent for “OncoMouse” transgenic for human cancer.

1992 Biotechnology company awarded patent for all forms of transgenic cotton. Groups concerned that this will limit the rights of subsistence farmers contest the patent several times.

1996 – 1999 Companies patent partial gene sequences and certain disease-causing genes for developing specific medical tests.

2000 With gene and genome discoveries pouring into the Patent and Trademark Office, requirements tightened for showing utility of a DNA sequence.

2003 Attempts to enforce patents on non-protein-encoding parts of the human genome anger researchers who support open access to the information.

2007 Patent requirements must embrace new, more complex definition of a gene.

2009 Patents on breast cancer genes challenged.

2010 Direct-to-consumer genetic testing companies struggle to license DNA patents for multigene and SNP association tests.

Patents on breast cancer genes invalidated.

2011 U.S. government considers changes to gene patent laws.

2013 U.S. Supreme Court declares genes unpatentable.

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The parents-to-be were very excited by the company’s promise:

“Bank your baby’s cord blood stem cells and benefit from

breakthroughs. Be prepared for the unknowns in life.”

The website profiled children saved from certain

diseases using stored umbilical cord blood. The statistics were

persuasive: More than 70 diseases are currently treatable with

cord blood transplants, and 10,000 procedures have already

been done.

With testimonials like that, it is little wonder that parents

collectively spend more than $100 million per year to store

cord blood. The ads and statistics are accurate but misleading,

because of what they don’t say. Most people never actually use

the umbilical cord blood stem cells that they store. The scientific

reasons go beyond the fact that treatable diseases are very rare.

In addition, cord blood stem cells are not nearly as pluripotent as

some other stem cells, limiting their applicability. Perhaps the most

compelling reason that stem cell banks are rarely used is based

on logic: For a person with an inherited disease, healthy stem cells

are required—not his or her own, which could cause the disease all

over again because the mutation is in every cell. The patient needs

a well-matched donor, such as a healthy sibling.

Commercial cord blood banks may charge more than

$1,000 for the initial collection plus an annual fee. However, the

U.S. National Institutes of Health and organizations in many other

nations have supported not-for-profit banks for years, and may not

charge fees. Donations of cord blood to these facilities are not to

help the donors directly, but to help whoever can use the cells.

Commercial stem cell banks are not just for newborns. One

company, for example, offers to bank “very small embryonic-like

stem cells” for an initial charge of $7,500 and a $750 annual fee,

“enabling people to donate and store their own stem cells when

they are young and healthy for their personal use in times of future

medical need.” The cells come from a person’s blood and, in fact,

one day may be very useful, but the research has yet to be done

supporting any use of the cells in treatments.

Questions for Discussion 1. Storing stem cells is not regulated by the U.S. government

the way that a drug or a surgical procedure is because it is a service that will be helpful for treatments not yet invented. Do you think such banks should be regulated, and if so, by whom and how?

2. What information do you think that companies offering to store stem cells should present on their websites?

3. Do you think that advertisements for cord blood storage services that have quotes and anecdotal reports, but do not mention that most people who receive stem cell transplants do not in fact receive their own cells, are deceptive? Or do you think it is the responsibility of the consumer to research and discover this information?

4. Several companies store stem cells extracted from baby teeth, although a use for such stem cells has not yet been found. Suggest a different way to obtain stem cells that have the genome of a particular child.

Bioethics: Choices for the Future

Banking Stem Cells: When Is It Necessary?

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xv

The Lewis Guided Learning System Learning Outcomes preview major chapter topics in an inquiry-based format according to numbered sections.

The Big Picture encapsulates chapter content at the start.

Chapter Openers vividly relate content to real life.

Key Concepts Questions follow each numbered section.

Figure 4.4 A Punnett square. A Punnett square illustrates how alleles combine in offspring. The different types of gametes of one parent are listed along the top of the square, with those of the other parent listed on the left-hand side. Each compartment displays the genotype that results when gametes that correspond to that compartment join.

Parent 2

T

T TT

t

T t

T t

t tt

Parent 1

Simplified T

T T tT T

t

t t tt T

Key Concepts Questions 4.1

1. How did Mendel deduce that units of inheritance for height segregate, then combine at random with those from the opposite gamete at fertilization?

2. Distinguish between a homozygote and a heterozygote; dominant and recessive.

3. What are the genotypic and phenotypic ratios of a monohybrid cross?

4. How do Punnett squares display expected genotypic and phenotypic ratios among progeny?

5. What is a test cross?

Figure 4.5 Test cross. Breeding a tall pea plant with homozygous recessive short plants reveals whether the tall plant is true-breeding ( TT ) or non-true-breeding ( Tt ). Punnett squares usually indicate only the alleles.

T

1/2 tall 1/2 short

All tall

t t tT t

t

t t tT t

T

t T tT t

T

t T tT t

T T or T t ? �

If T T If T t

t t

P1

F1

4.2 Single-Gene Inheritance Is Rare

Mendel’s first law addresses traits and illnesses caused by sin- gle genes, which are also called Mendelian or monofactorial. Single-gene disorders, such as sickle cell disease and muscular dystrophy, are rare compared to infectious diseases, cancer, and multifactorial disorders, most affecting 1 in 10,000 or fewer individuals. Clinical Connection 4.1 discusses some unusual single-gene traits.

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The Little Lady of Flores

The Nage people, who live on the island of Flores in

Indonesia, speak of the Ebu Gogo, short hairy people thought

to be mythical—until a team of Australian and Indonesian

archaeologists arrived in 2003. They discovered, 17 feet beneath

a cave floor, the near-complete skeleton of a female who fit the

legendary description, plus pieces of seven other individuals. The

ancient remains represent a people named Homo floresiensis.

The little people of Flores were half our height, with a brain

about half the size of ours but with well-developed frontal

lobes, suggesting that they were smart enough to use tools

and fire and to hunt. They must have arrived on the island

by raft, so some investigators suggest that the people had a

language to coordinate the journey. Homo floresiensis had

large teeth and feet, no chin, and a receding forehead. The

little lady weighed about 55 pounds.

The people may have exhibited “island dwarfism,” which is an

effect of natural selection on small, isolated island populations.

With limited resources, individuals who need less food are

more likely to survive to reproduce. Over time under these

conditions, average body size decreases. The little people

hunted local little elephants.

Evidence indicates that the Flores people lived on the

island from 95,000 to as recently as 12,000 years ago, but

Portuguese traders report having seen the people as recently

as the seventeenth century. Some researchers suggest that

they may still exist.

Learning Outcomes

16.1 Human Origins

1. How can DNA sequences provide information about our ancestry?

2. Describe our ancestors.

3. What can we learn from indigenous peoples about our origins?

16.2 Methods to Study Molecular Evolution

4. How do chromosome banding patterns and protein sequences reveal evolution?

5. What is a “molecular clock”?

6. How are mitochondrial DNA and Y chromosome sequences used to track human ancestry?

7. Explain how haplotypes provide clues to ancient migrations.

16.3 The Peopling of the Planet

8. What does mitochondrial Eve represent?

9. How did people expand out of Africa?

16.4 What Makes Us Human?

10. How does the human genome differ from the genomes of other primates?

11. What traits are unique to humans?

12. List genes that distinguish us from our closest relatives.

Human Ancestry and Evolution

Who were the little people of Flores?

C H A P T E R

16

Our genes and genomes hold clues to our deep past and our present diversity. How will our species continue to evolve?

The BIG Picture

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In-Chapter Review Tools, such as Key Concepts Questions, summary tables, and timelines of major discoveries, are handy tools for reference and study. Most boldfaced terms are consistent in the chapters, summaries, and glossary.

Bioethics: Choices for the Future and Clinical Connection boxes include Questions for Discussion.

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Final PDF to printer

Flipping the X ray showed Stefan Mundlos, MD, that his hunch was

right—the patient’s arms were odd-looking and stiff because the

elbows were actually knees! The condition, Liebenberg syndrome

(OMIM 186550), had been described in 1973 among members

of a five-generation white South African family (figure 1). Four

males and six females had stiff elbows and wrists, and short

fingers that looked strangely out of place. A trait that affects both

sexes in every generation displays classic autosomal dominant

inheritance—each child of a person with strange limbs had a 50:50

chance of having the condition too.

In 2000, a medical journal described a second family

with Liebenberg syndrome. Several members had restricted

movements because they couldn’t bend their huge, misshapen

elbows. Then in 2010, a report appeared on identical twin girls

with the curious stiff elbows and long arms, with fingers that

looked like toes.

In 2012, Dr. Mundlos noted that the muscles and tendons of

the elbows, as well as the bones of the arms, weren’t quite right in

his patient. The doctor, an expert in the comparative anatomy of

limb bones of different animals, realized that the stiff elbows were

acting like knees. The human elbow joint hinges and rotates, but

the knee extends the lower leg straight out. Then an X-ray scan

of the patient’s arm fell to the floor. “I realized that the entire limb

had the appearance of a leg. Normally you would look at the upper

limb X ray with the hand up, whereas the lower limb is looked at

foot down. If you turn the X ray around, it looks just like a leg,”

Dr. Mundlos said.

Genes that switch body parts are termed homeotic. They

are well studied in experimental organisms as evolutionarily

diverse as fruit flies, flowering plants, and mice, affecting the

positions of larval segments, petals, legs, and much more.

Assignment of body parts begins in the early embryo, when

cells look alike but are already fated to become specific

structures. Gradients (increasing or decreasing concentrations) of

“morphogen” proteins in an embryo program a particular region

to develop a certain way. Mix up the messages, and an antenna

becomes a leg, or an elbow a knee.

Homeotic genes include a 180-base-long DNA sequence,

called the homeobox, which enables the encoded protein to bind

other proteins that turn on sets of other genes, crafting an embryo,

section by section. Homeotic genes line up on their chromosomes

in the precise order in which they’re deployed in development, like

chapters in an instruction manual to build a body.

The human genome has four clusters of homeotic genes,

and mutations in them cause disease. In certain lymphomas,

a homeotic mutation sends white blood cells along the wrong

developmental pathway, resulting in too many of some blood cell

types and too few of others. The abnormal ears, nose, mouth,

and throat of DiGeorge syndrome (OMIM 188400) echo the

abnormalities in Antennapedia, a fruit fly mutant that has legs on

its head. Extra and fused fingers and various bony alterations also

stem from homeotic mutations.

The search for the mutation behind the arm-to-leg

Liebenberg phenotype began with abnormal chromosomes.

Affected members of the three known families were each missing

134 DNA bases in the same part of the fifth largest chromosome.

The researchers zeroed in on a gene called PITX1 that controls

other genes that in turn oversee limb development. In the

Liebenberg families, the missing DNA places an “enhancer”

gene near PITX1, altering its expression in a way that mixes up

developmental signals so that the forming arm instead becomes

a leg. Fortunately the condition appears more an annoying oddity

than a disease.

Questions for Discussion 1. What is the genotype and phenotype of Liebenberg

syndrome?

2. How can homeotic mutations be seen in such different species as humans, mice, fruit flies, and flowering plants?

3. Explain the molecular basis of a homeotic mutation and the resulting phenotype.

4. Name another human disease that results from a homeotic mutation.

Clinical Connection 3.1

When an Arm Is Really a Leg: Homeotic Mutations

Figure 1 The hands of a person with Liebenberg syndrome resemble feet; the arms resemble legs.

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xvi

Summary 11.1 Gene Expression Through Time and Tissue 1. Changes in gene expression occur over time at the molecular

and organ levels. Epigenetic changes to DNA alter gene expression, but do not change the DNA sequence.

2. Proteomics catalogs the types of proteins in particular cells, tissues, organs, or entire organisms under specified conditions.

11.2 Control of Gene Expression 3. Acetylation of certain histone proteins enables the

transcription of associated genes, whereas phosphorylation and methylation prevent transcription. The effect of these three molecules is called chromatin remodeling.

4. MicroRNAs bind to certain mRNAs, blocking translation.

11.3 Maximizing Genetic Information 5. A small part of the genome encodes protein, but the number

of proteins is much greater than the number of genes. 6. Alternate splicing, use of introns, protein modification, and

cutting proteins translated from a single gene contribute to protein diversity.

11.4 Most of the Human Genome Does Not Encode Protein

7. The non-protein-encoding part of the genome includes viral sequences, noncoding RNAs, pseudogenes, introns, transposons, promoters and other controls, and repeats.

8. Long noncoding RNAs control gene expression.

www.mhhe.com/lewisgenetics11

Answers to all end-of-chapter questions can be found at www.mhhe.com/lewisgenetics11 . You will also find additional practice quizzes, animations, videos, and vocabulary flashcards to help you master the material in this chapter.

Review Questions 1. Why is control of gene expression necessary?

2. Define epigenetics.

3. Distinguish between the type of information that epigenetics provides and the information in the DNA sequence of a protein-encoding gene.

4. Describe three types of cells and how they differ in gene expression from each other.

5. What is the environmental signal that stimulates globin switching?

6. How does development of the pancreas illustrate differential gene expression?

7. Explain how a mutation in a promoter can affect gene expression.

8. How do histones control gene expression, yet genes also control histones?

9. What controls whether histones enable DNA wrapped around them to be transcribed?

10. State two ways that methyl groups control gene expression.

11. Name a mechanism that silences transcription of a gene and a mechanism that blocks translation of an mRNA.

12. Why might a computational algorithm be necessary to evaluate microRNA function in the human genome?

13. Describe three ways that the number of proteins exceeds the number of protein-encoding genes in the human genome.

14. How can alternate splicing generate more than one type of protein from the information in a gene?

15. In the 1960s, a gene was defined as a continuous sequence of DNA, located permanently at one place on a chromosome, that specifies a sequence of amino acids from one strand. List three ways this definition has changed.

16. Give an example of a discovery mentioned in the chapter that changed the way we think about the genome.

17. What is the evidence that some long noncoding RNAs may hold clues to human evolution?

Applied Questions 1. The World Anti-Doping Agency warns against gene

doping, which it defines as “the non-therapeutic use of cells, genes, genetic elements, or of the modulation of gene expression, having the capacity to improve athletic

performance.” The organization lists the following genes as candidates for gene doping when overexpressed:

Insulin-like growth factor ( IGF-1 )

Growth hormone ( GH )

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Each chapter ends with a point-by-point Chapter Summary.

Review Questions assess content knowledge.

Applied Questions help students develop problem- solving skills.

Web Activities 1. Gene expression profiling tests began to be marketed

several years ago. Search for “Oncotype DX,” “MammaPrint,” or “gene expression profiling in cancer” and describe how classifying a cancer this way can improve diagnosis and/or treatment. (Or apply this question to a different type of disease.)

2. The government’s Genotype-Tissue Expression (GTEx; https://commonfund.nih.gov/GTEx/ ) project is a database

of gene expression profiles of 24 tissues (parts of organs) from 190 people who died while healthy.

a. What type of data are compared? b. Suggest a way that a researcher can use this type

of information.

3. Look up each of the following conditions using OMIM or another source, and describe how they arise from altered chromatin: alpha-thalassemia, ICF syndrome, Rett syndrome, Rubinstein-Taybi syndrome.

Forensics Focus 1. Establishing time of death is critical information in

a murder investigation. Forensic entomologists can estimate the “postmortem interval” (PMI), or the time at which insects began to deposit eggs on the corpse, by sampling larvae of specific insect species and consulting developmental charts to determine the stage. The investigators then count the hours backwards to estimate the PMI. Blowflies are often used for this purpose, but their three larval stages look remarkably alike in shape and color, and development rate varies with environmental conditions. With

luck, researchers can count back 6 hours from the developmental time for the largest larvae to estimate the time of death.

In many cases, a window of 6 hours is not precise enough to narrow down suspects when the victim visited several places and interacted with many people in the hours before death. Suggest a way that gene expression profiling might be used to more precisely define the PMI and extrapolate a probable time of death.

Case Studies and Research Results 1. To make a “reprogrammed” induced pluripotent stem

(iPS) cell (see figure 2.22), researchers expose fibroblasts taken from skin to “cocktails” that include transcription factors. The fibroblasts divide and give rise to iPS cells, which, when exposed to other transcription factors, divide and yield daughter cells that specialize in distinctive ways that make them different from the original fibroblasts.

How do transcription factors orchestrate these changes in cell type?

2. A study investigated “genomic signatures of global fitness” to identify gene expression patterns that indicate that a course of exercise is beneficial. In the study, sixty sedentary women representing different ethnic groups

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Web Activities encourage students to use the latest tools and databases in genetic analysis.

Forensics Focus questions probe the use of genetic information in criminal investigations.

Cases and Research Results use stories based on accounts in medical and scientific journals; real clinical cases; posters and reports from professional meetings; interviews with researchers; and fiction to ask students to analyze data and predict results.