Human Genes and Genomes: Science, Health, Society

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Dedicated to our children

Robert, Diana, David, and Alexa

And to our grandchildren

Suzannah, Sam, Eli, Celia, and Abraham

About the Authors

Leon E. Rosenberg has been a professor in the Department of Molecular Biology and the Woodrow Wilson School of Public and International Affairs at Princeton University since 1998. From September 1991 to January 1998, he was Chief Scientific Officer of the Bristol-Myers Squibb Company.

Prior to joining Bristol-Myers Squibb, Dr Rosenberg was dean of the Yale University School of Medicine, a position he had held since 1984. During his 26-year affiliation with Yale, he worked as a research geneticist, teacher, clinician, and administrator. In 1965, he was appointed assistant professor of medicine at Yale. He was named professor of human genetics, pediatrics, and medicine in 1972, the same year he helped establish the Department of Human Genetics at Yale and became its first chairman. A specialist in inherited metabolic disorders in children, Dr Rosenberg and his colleagues conducted pioneering laboratory investigations into the molecular basis of several inherited disorders of amino acid and organic acid metabolism.

Dr. Rosenberg received his BA and MD degrees, both summa cum laude, from the University of Wisconsin. He completed his internship and 1 year of residency training in internal medicine at Columbia-Presbyterian Medical Center in New York City. He then moved to Bethesda, Maryland, to begin a 6-year association as an investigator with the metabolism service of the National Cancer Institute.

Dr Rosenberg’s honors include election to the National Academy of Sciences and to the Institute of Medicine, recipient of the Borden Award from the American Academy of Pediatrics and of the Kober Medal from the Association of American Physicians, and honorary Doctor of Science degrees from the University of Wisconsin and the Mt Sinai School of Medicine. He was the medalist for the Australian Society for Medical Research in 2002. He is a past president of the American Society of Human Genetics, the Association of American Physicians, the Funding First Initiative of the Mary Lasker Trust, and the Association of Patient Oriented Research.

Diane Drobnis Rosenberg is the Chief Operating Officer of Meadowgate Farm Alpacas, LLC, in Lawrenceville, NJ. She has been active on numerous boards, including the Foundation for Health in Aging Board for the American Geriatrics Society, the Friends Board of the Institute for Advanced Study, and SAVE, a private Princeton animal shelter.

At companies such as McGraw-Hill, Elsevier Science Publishing, and Williams & Wilkins, Ms Drobnis Rosenberg acquired and published life sciences books and texts as well as medical journals. In 1990, she started a consulting firm that worked with medical societies on business arrangements for their journals.

Ms Drobnis Rosenberg was born in Washington, DC in 1944 and grew up in Evanston, Illinois. She is an Alumna of Wellesley College, where she majored in Biology, and also the University of Pennsylvania, where she studied Molecular Biology, having been awarded a NASA traineeship.

Foreword

The Rosenbergs, the authors of Human Genes and Genomes: Science, Health and Society, and I, share a deep admiration for Archibald Garrod (1857-1936), physician-scientist and student of human biology. I will explain, briefly, why Garrod and his ideas, deserve mention here and why he is so admired.

In 1908, Garrod held the prestigious Croonian Lectureship under the auspices of the Royal College of Physicians, London. The lectures themselves were delivered on four separate days and published separately in the journal Lancet. They were then published together as a book in 1908, with additional text, under the title Inborn Errors of Metabolism. Garrod used the Croonian Lectures to present his novel concept of inborn errors affecting metabolism. He illustrated it with his own findings gleaned from the careful study of patients harbouring one of four rare charter inborn errors: albinism, cystinuria, pentosuria, and alkaptonuria; the latter condition had already been used by Garrod, in an article published in 1902, to introduce the new theme of human chemical individuality. At the time, Garrod’s Croonian Lectures were salient primarily among biochemists; they were controversial for geneticists, because Mendelism was in abeyance among the biometricians; and they were almost irrelevant for the physicians in his audience. Today, the lectures are recognized as landmarks in the ever-evolving knowledge of human biology, biochemistry, genetics, and medicine.

Metabolism functions somewhere near the core of life itself in autonomous agents such as ourselves. Garrod saw metabolism as a dynamic process involving a normal chemical species (metabolites) distributed in and flowing through normal pathways which could be made variant by Mendelian inheritance. No small gift of understanding! Garrod’s insight was huge, yet at the time he would have known little or nothing about enzymes and genes for which even the names were still mysteries awaiting revelation at some distant future. Nonetheless, his insights were correct, and they were given coherence by later discoveries. With hindsight, we can see that Garrod had qualities to fit an aphorism from antiquity: the fox knows many things but the hedgehog knows one big thing (Archilocus 680-645 B.C.). Garrod’s unifying vision of human biology (the hedgehog in him) also encompassed its particularities (the fox in him). Accordingly, one could say that Garrod was a hybrid ‘hedgefox’ by nature.

A second, slightly enlarged, edition of Inborn Errors of Metabolism appeared in 1923, but Garrod’s hope that many new examples of these variant phenotypes would have been discovered did not materialize until 1935 when he was told about the discovery of phenylketonuria, regarded today as a classic example of a Mendelian inborn error of human metabolism.

Meanwhile, Garrod had been enlarging his awareness of variance at the interface between heredity and experience. In his famous essay of 1902 on the incidence of alkaptonuria, Garrod had begun to broaden the spectrum of illnesses, apparently explained in part by heredity, to include idiosyncratic reactions to food and drugs, as examples. He encapsulated the corresponding inborn susceptibility in the term diathesis. Garrod saw diathesis (or heredity) as a contributor to cause even when there was no overt pattern of Mendelian inheritance for the ailment. This prescient view was illustrated with examples of various complex disorders showing familial tendencies. Under the title Inborn Factors in Disease, Garrod gathered these subtle ideas together and published them in his second great book in 1931. This book was republished with extensive annotations in 1989 by Scriver and Childs, with a Foreword by Lederberg, under the title Garrod’s Inborn Factors in Disease (Oxford University Press).

I see Inborn Factors as the companion to "Inborn Errors", the two books serving as forerunners to medical genetics as we know it today. This explains our admiration for Garrod and his ideas. Unfortunately, the prematurity of these insights hindered their wider recognition and a paradigm shift in thinking was too long delayed.

Whereas inborn errors are relatively rare events in the population, we now know that inborn factors make enormous contributions to the corresponding burden of common diseases in human society. If Garrod gave us new ways to think about the causes of illnesses, we were also given better ways to answer an abiding question in health care: Why does this person have this ailment now? Garrod brought genetics into medical thinking. In his day, these were esoteric ways of knowing; today they are pragmatic and mainstream. To know about DNA and genes and about biochemical networks and genomes, has acquired resonance and relevance. To be aware of the genetic landscape that shapes us as autonomous organisms is not an esoteric exercise; it becomes a facet of human culture when it is a way of knowing the biological infrastructure of our personal and collective health and our being. While such knowledge is transforming, it is also being translated into useful tactics such as diagnostic tests, therapies, and practices to neutralize or even eliminate the disadaptive effects of our diseases. These are some of the whys and the whats of knowing more about human genetics, why the Rosenbergs have written this book, and why Dr. Rosenberg teaches his course at Princeton.

When we are better informed with greater knowledge, we may be able to answer, with greater wisdom, three questions posed by the poet T.S. Eliot:

Where is the life we have lost in living?

Where is the wisdom we have lost in knowledge?

Where is the knowledge we have lost in information?

(Choruses from the Rock, Part I, lines 15-17.)

After pondering these unsettling questions, the reader may find encouragement in four other often-cited lines of poetry by the same poet:

We shall not cease from exploration

And the end of all our exploring

Will be to arrive where we started

And know the place for the first time.

(Little Gidding: Lines 239-242, from Four Quartets).

While modern genetics and ancient heredity will not cease to permeate culture, there will always be room for the poetry.

I will end with a thought about the culture of science. Richard Feynman proposed that science is driven by a continual dialogue between sceptical inquiry and a sense of inexplicable mystery. May you, reader and student, always enjoy sceptical inquiry, yet never lose sight of mystery and its excitement.

Charles R. Scriver, MDCM FRS

Alva Professor Emeritus of Human Genetics,

McGill University

Preface

The decision to write this textbook was made in the earliest days of January, 2010, though it had been in our minds and lives for 36 years. This decision came about collaboratively as follows. LER was engaged in his perennial task of updating his one semester course for undergraduates at Princeton University, entitled Genes, Health, and Society. This year’s effort was unusually strenuous, aimed at complete integration of information about modern genomics with classical genetics. As he lamented that, in his view, none of the textbooks in the field were optimal for his course (too long or too short; too detailed or too brief; aimed at science majors rather than non-majors; for medical or graduate students, not undergraduates), his wife of 32 years, DDR, repeated advice she had given him before and throughout their marriage, Why not write your own book, then, with my assistance? And so we have.

AUDIENCE: This book is designed for use in a one-semester course particularly, though not exclusively, for college or university undergraduates. It should also be of use to some medical, dental, nursing, or graduate students, to prospective genetic counselors, and to interested members of the general public. It presupposes no prior exposure to the subject of human genes and genomes, aiming instead to present the principles of the field and to follow these with a discussion of its many applications and implications. If our aim is true, this book will be neither above the head of the non-major in science nor below the foot of those concentrating on the biological, chemical, or physical sciences.

THESIS: The syllabus for the Princeton course that inspired this textbook begins with two questions: Why should an educated person living in the twenty-first century know something about human genes and genomes? and What should they know? Here is our answer: The educated person should be conversant with human genes and genomes because it is scientifically exciting, esthetically elegant and beautiful, and increasingly relevant to every day life. We doubt that anyone will contest the view that genetics was the most thrilling of the sciences during the second half of the twentieth century and continues its dazzling pace in the twenty-first. Each seminal discovery (always rare) and the many important contributions that have followed them have changed the way we think about living organisms and have expanded the core of human knowledge. They have literally transformed our view of biological molecules, cells, organ, individuals, populations, and the evolution of the human species. For those fortunate enough to experience this scientific journey, it has been like taking a strenuous upward climb in the autumn, in that the shapes and colors of each panoramic view become more breathtaking the higher one climbs. Thus, it behooves an educated person to know something about genetics for the same reason that they should be aware of such other core subjects as mathematics, philosophy, history, literature, and music.

Another answer to the why question is the growing relevance of the science of genetics and genomics to health, medicine, and society. Our individual uniqueness begins with our genetic blueprint. Our health depends on the way our genes interact with our environment(s). Our myriad medical ailments result, in whole or in part, from genetic mutations. Our attitudes regarding the occasional explosive interfaces between science and religion are often shaped by the implications of discoveries in genetics and genomics to bioethics, morality, and law.

As for what an educated person should know, we believe that an understanding of the language of genetics and genomics is required for intelligent, critical evaluation of what one hears from a physician or politician, of what one reads in the newspaper or on the web, or of the personal decisions one makes about such things as marriage and reproduction. Complex language is what differentiates humans from all other species. Knowing something of the specialized language of genetics and genomics will, likewise, facilitate communication between individuals and among groups.

EDUCATIONAL CHALLENGES: Human Genetics is a complex subject and becoming more so. This fact presents challenges for those who teach this subject as well as to their students.

Teachers need to:

• recognize that some of their students have little grounding in the biological sciences, yet have an interest in human genetics as great as that of students familiar with the subject;

• present the concepts that the subject is built on in such a way that its applications and implications follow in an orderly and coherent way;

• include the mathematical underpinnings of such subjects as risk assessment, linkage, and genotype frequency;

• be aware of the religious and political forces that make some topics in human genetics charged and controversial;

• use examples from the clinic, the media, and personal experiences to make the subject live and breathe.

Students need to:

• understand that learning the language and concepts of human genetics is required before its more accessible applications and implications can be understood and debated;

• remember that much of the information they have gained about genetics at the dinner table or from the media is mythologic or just plain wrong;

• embrace the numerical aspects of the field because they are both its underpinnings and its means of problem-solving;

• distinguish among such critical words as cause, risk, probability, and susceptibility.

ORGANIZATION: This book is composed of 19 chapters arranged in a logical progression in which each successive chapter builds on the one(s) before. There are three main parts: core concepts; genetic disorders; and genes in populations and individuals. To enrich the text, the book contains 74 photographs, 170 line drawings, and 61 tables. Further, there are 21 boxed entries, which are entitled intersections, amplification, or implications; they are designed to highlight special topics.

EDUCATIONAL TOOLS: Each chapter is followed by a set of review questions and exercises that allow students to test their understanding. Answers to all of these questions are found at the end of the book. The book’s end also contains the following: a list of classic and contemporary readings; a comprehensive glossary; and a thorough, well organized index.

In addition to these embedded tools, there are two varieties of web-based resources. The first is the following list of websites containing much useful information about general or specific topics in the field of human genetics and genomics.

General Information

American Society of Human Genetics

www.ashg.org

American College of Medical Genetics

www.acmg.org

Genetics and Public Policy Center

www.DNApolicy.org

National Cancer Institute

www.cancer.gov

National Institutes of Health

www.nih.gov

National Society of Genetic Counsellors

www.nsgc.org

Online Mendelian Inheritance in Man

www.omim.org

Specific Topics

American Society of Gene Therapy

www.asgt.org

Bioethics Blog

http://blog.bioethics.net

Council for Responsible Genetics

www.councilforresponsiblegenetics.org

Innocence Project

www.innocenceproject.org

International Society for Stem Cell Research

www.isscr.org

National Library of Medicine

www.medlineplus.gov

National Organization for Rare Disorders

www.rarediseases.org

The second source is the companion website for the book provided by Elsevier – http://www.elsevierdirect.com/9780123852120. This site contains all images in electronic format for convenience in teaching, direct links to the above referenced sites of interest and additional information about the book.

CONTENT: The following notes provide a thumbnail sketch of the content of each chapter, and include a few, representative illustrations.

Chapter 1 frames the field by raising commonly asked questions about such topics as eye-color, hair-color, and height. It is aimed at drawing the student into the subject.

Chapter 2 presents a complete list of all core concepts which lead off each subsequent chapter. It is a distillate of the entire book, useful to many but not all readers.

Chapter 3 explains what we mean when we say that genetics is the science of heredity and individual variation. It focuses on the unity of living things, and on the historical landmarks of the field from Mendel to the present day.

Chapter 4 describes where genes are found (in chromosomes) and what they program (cell division, fertilization, embryonic and fetal development, cellular differentiation, and cell death). It makes clear what we mean by the phrase, chromosomal basis of heredity.

Figure 4.11 Fertilization of an egg by a sperm. As a single sperm penetrates the corona radiata and zona pellucida, a series of chemical reactions facilitate penetration of the plasma membrane and prevent other sperm from gaining entry. After fertilization has occurred, meiosis II in the egg is completed and the male and female pronuclei form.

Chapter 5 tells the story of how genes are transmitted from one generation to the next. It highlights the life and work of the first geneticist, Gregor Mendel, and of the modes of inheritance that bear his name.

Chapter 6 moves to the molecular level. It deals with DNA from many vantages: how we came to know that it is the stuff of genes; how it is constructed; how it replicates; how we distinguish between a gene and a genome; how scientists came to sequence the entire human genome and decipher some of its secrets.

Figure 6.21 Creating recombinant DNA molecules with plasmid vectors. A DNA fragment, prepared by digestion with Eco R1, is joined to an Eco R1 cleaved plasmid; the recombinant plasmid then transforms a bacterial cell, where the plasmid is replicated as the bacteria proliferate; the recombinant plasmids are isolated and the cloned donor fragments of DNA pooled.

Chapter 7 addresses the function of genes and genomes. It presents the central dogma of molecular biology by which information in DNA is converted to its functional elements—proteins. To amplify this central theme, such subjects as differential gene expression and gene silencing are presented.

Chapter 8 defines the term, mutation, as a heritable change in the nucleotide sequence of DNA. It underscores that mutations of many kinds exist and produce positive and negative phenotypes, as well as being the driving force for biological evolution.

Figure 8.1 Classes of mutations affecting DNA structure. See text for further definition of substitution, insertion, deletion, and inversion.

Chapter 9 lays out the incontrovertible evidence for biological evolution. It explains what is meant by decent from a common ancestor, and construction of life trees. It argues that creationism and intelligent design are supernatural constructs, not evidence-based science.

Chapter 10 asks why no two human beings are genetically identical, and underscores how far we are from answering the profound question of individual uniqueness.

Chapter 11 introduces the broad subject of genetic disorders, classifies them, and then focuses on abnormalities of chromosome number or structure. It underscores that most chromosomal defects occur during meiosis and that only a small minority of such defects are compatible with life, and even fewer, with good health.

Figure 11.4 Consequences of non-disjunction occurring in either meiosis I or meiosis II. A single pair of chromosomes is depicted—the paternal homologue is in pink, the maternal homologue in red. As discussed in the text, the homologues present in the two trisomic zygotes are not identical.

Chapter 12 states that single-gene mutations have already been discovered at more than 2,000 loci (out of a total of 21,000). These mutations have variously positive, negative, or neutral phenotypic effects. They have provided scientists and physicians with invaluable information about biological processes and disease mechanisms.

Chapter 13 introduces the fundamental theme that most common traits and most common disorders result from the interactions of two or more genes with the external environment (multifactorial traits). It points out that this subject is at the frontier of human genetic research and that genomic and epigenomic approaches have merely offered a tiny crack in the door toward its understanding.

Chapter 14 states that exploration of the human genome has recently revealed a new class of genetic disorders – namely that due to previously unrecognized architectural changes in the genome typified by extra gene copies, missing gene copies, misplaced chromosomal segments, and other changes referred to as copy number variations.

Figure 14.4 Genotypes and phenotypes in α-thalassemia. Top: normal people have four copies of α-globin genes (2A1, 2A2). Bottom: in the absence of all four copies (shown as empty boxes), infants succumb in utero or at birth with hydrops fetalis (meaning fluid accumulation in the fetus). Four intermediate genotypes reflect progressive loss of A1 or A2 copies. See text for details.

Chapter 15 states that about 5% of all live-born humans have major or minor congenital abnormalities (also called birth defects). It touches on the huge subject of how genes control the prenatal development of multicellular organisms. It points out that birth defects are generally caused by chromosomal, single-gene, or multifactorial abnormalities, but that a small fraction result from teratogens in the environment of pregnant women.

Chapter 16 discusses the concept that cancer is a genetic disease, usually caused by mutations in somatic cells rather than in germ cells. It defines the phenotypic features of the cancer (malignant) cell, and points out that viruses, chemicals, and other environmental insults can lead to the appearance of cancer genes which lead cells to grow out of control.

Figure 16.6 The two major forms of cancer-causing genes. An oncogene acts dominantly; mutation of one allele alters the expression of its gene product. A tumor suppressor gene acts recessively; mutation of both alleles are required before abnormal gene expression is produced. Mutation of one allele only does not disturb function.

Chapter 17 brings the presentation of genetic disorders to a close by discussing the various means of detecting and treating such conditions. It underscores that detection may be carried out throughout the human life cycle and that many treatment modalities exist – with variable effectiveness. It summarizes the state of our information about the potential of gene therapy and of the use of embryonic stem cells.

Chapter 18 shifts the focus from individuals and families to populations – including the entire human species. It introduces the mathematical cornerstone of population genetics, mentions its exceptions, and shows how it is used in clinical and counseling settings. It concludes by discussing human origins, migrations, and genetic variability within and among ethnic groups and races.

Chapter 19 uses particular examples to forecast the view that personalized genetics and genomics is more than a slogan. It posits that the means are, or soon will be, at hand to identify susceptibility to many conditions, to explain the individual efficacy and adverse effects of pharmaceuticals, and to offer progressively more information about the central question: why am I different from every other human being on planet Earth.

Acknowledgements

Recognizing individuals and groups who have, in one way or another, contributed to this project is both necessary and unsatisfying. It is necessary because this textbook would not have been completed without them. It is unsatisfying because merely listing them conveys no sense of the gratitude we feel for their contributions—particularly for those people who don’t even know that they have made a difference. With this disclaimer, we recognize the following.

Author of the Foreword. We can think of no one more appropriate to write the foreword to this book than Charles Scriver, a distinguished human geneticist, and our compatriot, friend, and confidant of many decades’ duration.

Authors of prior books. We benefited greatly from the efforts of others who have authored outstanding textbooks in the field of genetics in general, and human genetics in particular. These include T. Gelehrter, F. Collins, and D. Ginsburg, Principles of Medical Genetics; D. Hartl and E. Jones, Genetics: Analysis of Genes and Genomes; L. Hartwell, L. Hood, M. Goldberg, A. Reynolds, L. Silver, and R. Veres, Genetics: From Genes to Genomes; R. Lewis, Human Genetics: Concepts and Applications: E. Mange and A. Mange, Human Genetics; R. Nussbaum, R. McGinnis, and H. Willard, Thompson and Thompson’s Genetics in Medicine.

Readers and reviewers. Early on, several people read drafts of chapters and offered criticism and encouragement: Arianna D’Angelo (who was also instrumental in preparing the glossary), Daniel Drobnis, and Steve Hanks. As the book neared completion, several colleagues graciously read the entire book and helped us see things that were unclear or in error. We therefore owe much to Mike Dougherty, Margretta Seashore, and Hunt Willard.

Secretarial expertise. We are grateful to Amanda Denzer-King for her organizational and technical expertise regarding a number of the book’s components (text, figures, tables, captions, and additional readings). Gail Huber and Ellen Brindle-Clark also provided valuable secretarial help at critical moments.

Elsevier Publishing Company. Several of our publisher’s staff tolerated the authors’ constant prodding with (generally) good humor—and did some prodding of their own: first and most constant, Christine Minihane (acquisitions editor), Ceil Nuyianes (art manager), Marie Dean (artist), Jessika Bella-Mura (developmental editor), Rogue Shindler (project manager), Caroline Johnson (production manager), and Sue Armitage (copy editor). Together, they and their many associates underscore the meaning of the word globalization in the world of scientific publishing. We thank them, wherever they are.

Colleagues. We could write a decent-sized book of its own to recognize the literally hundreds of colleagues in the world of human genetics who have interacted with one or both of us over the years and who have, indirectly or directly, led us toward this project. They include scientific collaborators, university leaders, academic comrades, and teaching assistants. We know who they are, and are certain that many of them could identify their anything-but-trivial contributions.

Students. This book would not have been written without the stimulus provided by the few thousand medical students at the Yale School of Medicine and, more recently, the several hundred undergraduates at Princeton University who were taught by LER. These latter students have caused the compass of LER’s career to point away from laboratory research, administration, and public advocacy and toward what it means to be a responsible, committed, full-time educator.

Table of Contents

Cover Image

Title

Copyright

Dedication

About the Authors

Foreword

Preface

Acknowledgements

Part 1 Introduction and Core Concepts

Chapter 1 Framing the Field

Rationale for Studying Genetics and Genomics

Why Study Human Genetics and Genomics Now?

Divergent Public Reactions to the Field

Anticipated Returns on Educational Investment

Chapter 2 Introducing the CORE CONCEPTS

Chapter 3: Genetic Variability

Chapter 4: Growth, Development, and Reproduction

Chapter 5: Transmission of Genes

Chapter 6: Structure of Genes, Chromosomes, and Genomes

Chapter 7: Expression of Genes and Genomes

Chapter 8: Mutation

Chapter 9: Biological Evolution

Chapter 10: Human Individuality

Chapter 11: Chromosome Abnormalities

Chapter 12: Single-Gene Defects

Chapter 13: Multifactorial Traits

Chapter 14: Disorders of Variable Genomic Architecture

Chapter 15: Birth Defects

Chapter 16: The Genetics of Cancer

Chapter 17: Detection and Treatment of Genetic Disorders

Chapter 18: Population and Evolutionary Genetics

Chapter 19: Personalized Genetics and Genomics

Chapter 3 Genetics

Heredity and Variation

History

Conservation of Genetic Information

Human Variation

Chapter 4 Growth, Development, and Reproduction

Chromosomes: Number and Nature

Cell Division

Prenatal Development

Chapter 5 Transmission of Genes

Familial Similarities

Mendelian Inheritance

Applying Principles of Gene Segregation to Genetic Counseling

Exceptions to Expected Mendelian Patterns

Mitochondrial Inheritance

Chapter 6 Structure of Genes, Chromosomes, and Genomes

Gene Composition

From Genes and Chromosomes to Genomes

Chapter 7 Expression of Genes and Genomes

Gene Expression: History of Research

The Ribonucleic Acids (RNAS)

The Genetic Code

Chapter 8 Mutation

Nature of Mutations

Chapter 9 Biological Evolution

Historical Evidence Supporting the Theory of Biological Evolution

Evolutionary Principles

Molecular Evolution

Chapter 10 Human Individuality

Uniqueness

Early Observations Regarding Uniqueness

Lessons from Genomics

Part 2 Genetic Disorders

Chapter 11 Chromosome Abnormalities

Introduction to Cytogenetics

Clinical Indications for Chromosome Analysis

Impact of Chromosome Abnormalities on Health

Types of Chromosome Abnormalities

Illustrative Examples

Chapter 12 Single-Gene Defects

Archibald Garrod

Terms and Principles

Panorama of Single-Gene Defects

Illustrative Examples

Chapter 13 Multifactorial Traits

Definitions and Formulations

Determining the Role of Genes

Identification of Specific Susceptibility Alleles

Illustrative Examples

Chapter 14 Disorders of Variable Genomic Architecture

Architecture of the Genome

Human Genomic Variation

Illustrative Examples

Chapter 15 Birth Defects

Introduction

Embryonic Development

Developmental Genetics

Teratogens

Illustrative Examples

Chapter 16 The Genetics of Cancer

Overview

Biology of Cancer

Cancer Genetics

Cancer Genes

Genomic Approaches to Cancer

The Environment and Cancer

Illustrative Examples

Chapter 17 Detection and Treatment of Genetic Disorders

Detection

Genetic Counseling

Treatment

Gene Therapy

Stem Cell Therapy

Part 3 Populations and Individuals

Chapter 18 Population and Evolutionary Genetics

Terminology

The Hardy-Weinberg Law

Factors that Perturb Hardy-Weinberg Equilibrium

Ancestry and Disease in the Genomic Era

Evolution in Populations

Societal Debates about Evolution: Science Versus Religion

Chapter 19 Personalized Genetics and Genomics

DNA Fingerprinting

Genetics and Medicines

Pharmacogenetics

Pharmacogenomics

Direct-to-Consumer Genomic Tests

Glossary

Additional Reading

APPENDIX 1. Answers to Review Questions

APPENDIX 2. Credits and Permissions

Index

PART 1

Introduction and Core Concepts

Chapter 1 Framing the Field

Chapter 2 Introducing the CORE CONCEPTS

Chapter 3 Genetics

Chapter 4 Growth, Development, and Reproduction

Chapter 5 Transmission of Genes

Chapter 6 Structure of Genes, Chromosomes, and Genomes

Chapter 7 Expression of Genes and Genomes

Chapter 8 Mutation

Chapter 9 Biological Evolution

Chapter 10 Human Individuality

Chapter 1

Framing the Field

Chapter Outline

Rationale for Studying Genetics and Genomics

Why Study Human Genetics and Genomics Now?

Divergent Public Reactions to the Field

Anticipated Returns on Educational Investment

Have you ever asked yourself questions such as these?

• Why are some people short, and others tall, and why are some children of tall parents short (Figure 1.1)?

FIGURE 1.1 Willie Shoemaker, a famous horse racing jockey, and Wilt Chamberlain, a famous NBA basketball player. Even though they dressed alike, their differences in height, weight, and skin color are discernable. Willy’s weight was under 100 lbs, and he was only 4 feet 11 inches tall, while Wilt’s weight was 275 lbs and he was 7 feet 1 inch tall. Multiple genes working together with the environment are responsible for all these differences, as well as some that are not as visible, such as susceptibility to disease.

• Why is red hair so much more common in the Scottish or Irish than in the Chinese or Japanese (Figure 1.2)?

FIGURE 1.2 This young woman has a relatively common variant of the gene that codes for a protein called the melanocortin 1 receptor. This causes her to have red hair, fair skin, and freckles.

• Is it true that a blue-eyed child must have two blue-eyed parents (Figure 1.3)?

FIGURE 1.3 A healthy blue-eyed boy whose parents both have blue eyes. Some blue-eyed people have brown-eyed or green-eyed parents.

• What does being a carrier for cystic fibrosis mean?

• Should all women be tested for genes that predispose to breast cancer?

• How does DNA fingerprinting exonerate people charged with murder?

• Is direct-to-consumer genetic testing valid and useful?

• What does the Genetic Information Nondiscrimination Act (GINA) prohibit?

• Why is the discipline of genetics so embroiled with societal controversies about stem cell research or the teaching of evolution?

These questions will be answered in this text. The science behind these answers is detailed, complex, and has important implications for laboratory research, clinical practice, and social issues.

Rationale for Studying Genetics and Genomics

In our view, it is incumbent on an educated person living in the 21st century to be familiar with the principles of science in general, and of genetics, in particular. We hold this view for many reasons. First, the study of genetics and genomics explores our biologic universe today in the same excitement-capturing way that astrophysics explored our physical universe yesterday. Rather than seeing stars and planets, geneticists see genes, genomes, cells, and organisms. Rather than landing men on the moon, geneticists now walk the human genome in search of landmarks. Rather than planning trips to Mars, geneticists contemplate the mystery of individual uniqueness, in scientific, not just philosophical, terms. In the nearly 60 years since Watson and Crick proposed the double helical structure of DNA (deoxyribonucleic acid) (Figures 1.4, 1.5), the molecule of heredity, wave after wave of discoveries have made genetics the most thrilling field in the sciences, perhaps in all human endeavors. And that is why an educated person must understand it.

FIGURE 1.4 Ball-and-stick models of the DNA double helix. The structural elegance is obvious; the details will be discussed in Chapter 6 .

FIGURE 1.5 Looking down through the center of a model of DNA’s double helix. The details will be discussed in Chapter 6 . The colors match those in Figures 1.4A .

Second, the study of the genomes of Homo sapiens and hundreds of other species has provided powerful—indeed incontrovertible—evidence for biological evolution from a common ancestor and for the mechanism of natural selection. It grounds the study of human origin and early migration, and reminds us that evolution is not done, but continues in us.

Third, there is much more than scientific excitement here. There is growing relevance to health, disease, and disability. Much of who we are, where we came from, and where we aregoing comes down to our genes and genomes. They define our biologic boundaries, or, to paraphrase Shakespeare, what our flesh is heir to. We will, increasingly, be able to use genetic information to make health-related decisions. Thus, awareness is a prerequisite for living a healthy life.

Why Study Human Genetics and Genomics Now?

The previous paragraphs offer a rationale for understanding genetics. But why now, and why human genetics? Without doubt, much that we know has been learned from bacteria, plants, yeast, flies, worms, and mice. Learning from these organisms will continue. Today, however, we can apply this fundamental information to humans and ask about humanness in all its complexity:

• about the relationship between the size of the human brain and the fraction of our genome expressed in it;

• about how our immune system wards off pathogenic organisms—even ones that we’ve not been exposed to before;

• about how normal traits are transmitted from parents to children;

• about why some traits cluster in certain populations, but not in others;

• about thousands of rare and common disorders resulting from deleterious mutations in our genes;

• about the value of and rationale for premarital, prenatal, and neonatal testing for genetic disorders;

• about genetic influences on beneficial and adverse responses to medications;

• about the benefits and risks of direct-to-consumer information concerning our own genome;

• about a near future when it will be possible to have one’s complete genome sequence determined for $1,000 or less using ever more sophisticated automated gene sequencing machines (Figure 1.6).

FIGURE 1.6 Automatic DNA sequencing machine. Its output must be linked to high-speed computer equipment. Machines like this one have lowered the cost of complete DNA sequencing in humans by more than 100,000 fold already, and will reduce the cost further.

Every one of these topics has moved out of the laboratory, the clinic, and the classroom to the public square. Not a day goes by without some mention of genes and genomes in print or on the Internet; in news media or on blogs; in movies or on television. Distinguishing fact from fiction (or fantasy), or telling the difference between understanding and misunderstanding, requires a frame of reference and some knowledge of terms and concepts.

INTERSECTIONS: BIOETHICS

The Unfortunate Misuse of Human Genetics

The smallest genetic differences among people, real or imagined, can sometimes lead to tragic actions. The conflict between the Tutsi and Hutu people of the country of Rwanda in central Africa illustrates this. Recent genetic studies indicate that a close ethnic kinship exists between these two tribes, generations of gene flow obliterating any clear-cut physical or genetic differences between them.

When the Belgian government and its colonial power seized control of Rwanda in 1916, they created a strict system of racial classification, dividing the previously unified population and putting one group (Tutsi) above the other (Hutu). Conducting a census, the colonialists classified the people throughout Rwanda based on a phenotypic (observable characteristics) scheme. This classification was based on nothing more than the size of the nose, color of the eyes, and height. People with a longer nose, lighter eyes, and greater height were said to be Tutsi. They were given positions of greater authority and opportunity, as well as favorable land possession. The result of splitting the population of Tutsis and Hutus in this way was a conflict between the different groups, particularly in 1994, that has lasted into the 21st century, resulting in the deaths of hundreds of thousands of people. That the horror of this recent genocide should have been based on scientifically spurious discrimination is both cruel and ironic

The size of the nose and the color of the eyes were factors that determined whether a person was classified as Hutu, Tutsi or Twa.

Divergent Public Reactions to the Field

An unusually wide array of public reactions has greeted the sometimes breathless pace of discovery in genetics and genomics. Most people take hope from the field in the form of scientific discoveries that tell us about the world we live in, in understanding the maladies that beset us throughout our lives, and in development of a personalized health care system.

A minority of the population sees the field in darker hues. Some doubt that scientists will describe their work candidly and without hype, or that scientists will conduct their work within accepted ethical boundaries. Other people have fears, not just doubts—they fear that employers, insurers, and law enforcement personnel who have access to genetic information will intrude upon their privacy; they fear that novel reproductive technologies such as in vitro fertilization (IVF) and pre-implantation genetic diagnosis (PGD) may be the opening wedge toward the end of sexual reproduction. Still others see in neonatal screening and genetic counseling the specter of neo-eugenics (manipulating human mating and reproduction to improve the human species) and runaway genetic determinism. Finally, some people are unalterably opposed to the field for moral and religious reasons. They may reject prenatal diagnosis and embryonic stem cell use, for example, and, by extension, everything else about the applications of genetics to individual choices.

It is not difficult to account for the widely divergent views just mentioned—hopes, doubts, fears, and opposition. Fundamentally, the divergence depends on one’s view of science. If one believes that science can improve the world we inhabit through understanding it, then advances in genetics and genomics will be perceived in a positive, even exuberant, way. But the more muted one’s belief in the power to make things better, the greater the likelihood that hopes will be transmuted to other elements. Lack of trust in science and scientists may provoke doubts. Frank mistrust will generate fears. Those who desire supernatural (rather than natural) explanations for human events may be inclined to see genetics as an attack on their religious, moral, and/or ethical precepts and, therefore, seek to see the field impeded, even halted.

Anticipated Returns on Educational Investment

This book will allow the student to comprehend the language, the direction, and the uncertainties in the field of genetics and genomics. It will help distinguish between such critical words as cause and susceptibility, and what is meant by necessary and sufficient. It will remind students of those instances when geneticists halted their own work on recombinant DNA technology, germ line gene therapy, reproductive cloning, and more, because they were concerned that the benefits in the work were exceeded by the risks. It will allow students to interpret and criticize what they encounter in the media and, thereby, be able to develop an informed position on a wide range of topics that will affect their lives.

REVIEW QUESTIONS AND EXERCISES

1. Discuss briefly four reasons why the field of human genetics has been at the forefront of science and medicine during the past half century.

2. Depending on one’s point of view, the field of human genetics either raises hopes or provokes fears. Discuss briefly three kinds of hopes and three kinds of fears.

3. As each new genetic technology has been developed, it has run into intense opposition from a segment of society. Describe briefly three such technologies and the origin of the opposition engendered.

4. An article in a major US newspaper was entitled Gene Screen: Will We Vote Against a Candidate’s DNA?

a. Is this headline mere attention grabbing? Why, or why not?

b. What societal changes would have to occur before mandating disclosure of a candidate’s genome sequence would be appropriate—if ever?

Chapter 2

Introducing the Core Concepts

Chapter Outline

Chapter 3: Genetic Variability

Chapter 4: Growth, Development, and Reproduction

Chapter 5: Transmission of Genes

Chapter 6: Structure of Genes, Chromosomes, and Genomes

Chapter 7: Expression of Genes and Genomes

Chapter 8: Mutation

Chapter 9: Biological Evolution

Chapter 10: Human Individuality

Chapter 11: Chromosome Abnormalities

Chapter 12: Single-Gene Defects

Chapter 13: Multifactorial Traits

Chapter 14: Disorders of Variable Genomic Architecture

Chapter 15: Birth Defects

Chapter 16: The Genetics of Cancer

Chapter 17: Detection and Treatment of Genetic Disorders

Chapter 18: Population and Evolutionary Genetics

Chapter 19: Personalized Genetics and Genomics

To participate in discussions about genes, genomes, health, and society intelligently, we must understand the principles and language of the field.

• When we say that a mutation in gene A causes disease B, we must understand what a mutation is, how mutations occur, and why and under what circumstances they may cause disease.

• When the Wall Street Journal publishes an article entitled, Gene May Foil AIDS Virus, we must understand the relationship between genes and the environment and realize that some mutations can be beneficial, while others are deleterious.

• When for-profit companies market direct-to-consumer analysis of your genome using SNPs (single-nucleotide polymorphisms, pronounced snips), we must know the difference between genes and genomes and understand what SNPs are and gauge their importance.

• When several groups claim to have "cloned human beings, we must ask, What’s the scientific evidence? and Should human cloning even be attempted?"

• When people say that geneticists are playing God, we must ask how anyone who believes that God is omnipresent and omnipotent can imagine any human masquerading as God.

The next 17 chapters will discuss, in some detail, the core concepts that attempt to offer a basis for considering answers to the above questions. To set the stage for this discussion and to allow the student to appreciate each concept’s and each chapter’s relationship to one another, the concepts will simply be stated here. You will note that some chapters have more than one core concept. Taken together, the core concepts provide a concise summary of this book.

Chapter 3: Genetic Variability

Genetics is the science of heredity and inherited variation. It considers the biological information all living organisms require to grow, develop, reproduce, and die. It considers, as well, how traits are transmitted from one generation to the next. The chemical nature of this information is the same in organisms as simple as microbes and as complex as man.

Chapter 4: Growth, Development, and Reproduction

All organisms package their genetic or genomic information in tiny cellular structures called chromosomes. The relationship between the words genome, chromosome, and gene may be thought of as a set of Russian dolls: a genome is composed of a set of chromosomes; a chromosome is composed of a set of genes; a gene is composed of a set of nucleic acids. In humans, and other eukaryotes (organisms composed of one or more cells containing a visible nucleus and organelles) which reproduce sexually, chromosomes are paired, one inherited from each parent. Human cells contain 23 pairs of chromosomes, for a total of 46. These diploid cells—cells that contain two copies of every chromosome—transmit their chromosomes during two kinds of cell division: mitosis and meiosis. In mitotic cell division, which occurs in all cells of the body, each "daughter cell" receives the identical chromosome complement of its parent cell. In meiosis, which occurs only in germ cells (reproductive cells), the diploid number (46) is halved, producing haploid gametes (cells that will fuse during fertilization), each with 23 chromosomes. Inherited variation between any two people is largely a function of two events that occur during meiosis: random chromosome separation and crossing over between members of each chromosome pair. Reproduction proceeds through the union of gametes, an oocyte (egg) from the female and a sperm from the male. The fertilized egg, or zygote, is diploid, as are all other body cells. Prenatal and postnatal development occurs through mitosis, which is how the single-cell zygote develops into a 40-billion cell newborn and a 100-trillion-cell adult.

Chapter 5: Transmission of Genes

Traits are transmitted from one generation to the next by genes. The Austrian monk, Gregor Mendel, discovered the basic rules of this transmission—that is, gene segregation and assortment—in the mid-nineteenth century by studying pea plants. Trait transmission in human pedigrees follows the same rules. Traits attributable to single genes (referred to as "Mendelian traits") are inherited as dominants or recessives. They may be autosomal or sex-linked. Traits attributable to multiple genes and those demonstrating imprinting or maternal inheritance display more complex patterns.

Chapter 6: Structure of Genes, Chromosomes, and Genomes

Genes are the units of inheritance. They are composed of DNA (deoxyribonucleic acid). Genes store information in linear DNA molecules composed of a four-letter chemical alphabet–composed of the bases G (guanine), C (cytosine), A (adenine), and T (thymine), which form the unique part of nucleotides, and which give each gene its unique function. Each gene has a unique sequence of these nucleotides, which, in turn, underlies its unique function. The DNA molecule is a double strand of nucleotides carrying complementary G-C or A-T base pairs. The complementarity of double-stranded DNA is the key to understanding how DNA functions in inheritance.

Within the cells of an organism, DNA molecules carrying genes are assembled into chromosomes: organelles composed of DNA and associated proteins. The sum total of genes and chromosomes in each cell is its genome. The nuclear human genome consists of 24 distinct kinds of chromosomes, composed of 6 billion nucleotides and about 21,000 genes. Only about 2% of the DNA in the human genome is composed of genes that encode proteins. The remainder is comprised of nucleotide sequences with variably understood regulatory and evolutionary significance.

Genomics, the study of whole genomes, was made possible by determining the complete DNA sequence of humans—and that of about 400 other organisms. This triumph of modern genetics, facilitated by employing old technologies (such as gene cloning, restriction mapping, gel electrophoresis) and new ones (such as high throughput DNA sequencers and power computational tools)—is beginning to reveal the kinds and extent of variation in DNA structure not previously anticipated and not yet well understood. Already, however, the study of remarkably common single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) is providing us with information about mechanisms of susceptibility to many human traits and disorders.

Chapter 7: Expression of Genes and Genomes

The central dogma of gene action is abbreviated: DNA→RNA→Protein. Genes transmit their information by being transcribed, i.e., their DNA codes for a complementary RNA referred to as messenger RNA (mRNA). In turn, mRNAs are edited, leave the nucleus, and are translated into proteins—the molecules largely responsible for the functions cells carry out. Translation occurs according to a universal genetic code: the sequence of nucleotides in mRNA, read as triplets (called codons) that specify the sequence of amino acids in proteins. This fundamental pathway of gene expression is modulated such that only a subset of genes is active in any one tissue—thereby explaining differentiation, that is, the structural and functional differences between, for example, a brain cell and a heart cell. Gene expression may be modified in a number of ways: by changes in DNA primary structure such as mutations; by chemical (epigenetic) modification of DNA; and by interference with mRNA structure or function produced by small RNA species, called siRNAs and miRNAs.

Chapter 8: Mutation

A mutation is a heritable change in the nucleotide sequence or arrangement of DNA. In the positive, evolutionary sense, mutations are responsible for the selective advantage that one species gains over another. In the negative sense, mutations cause or increase susceptibility to thousands of human disorders. Mutations can occur at three different levels: genome, chromosome, and gene. Genome mutations result from missegregration (failure of chromosomes to properly segregate) during meiosis and produce changes in chromosome number. Chromosome mutations are caused by rearrangements in the structure of a chromosome, such as translocations or deletions. Gene mutations alter the base sequence of a gene. Mutations occur in germ cells, somatic cells, and mitochondria. Germ-line mutations affect DNA in all cells and are transmitted to offspring. Mitochondrial mutations affect mitochondrial DNA, all of which is inherited from the mother’s egg; accordingly, they are inherited maternally. Somatic mutations affect cells in a single tissue and are not transmitted to the next generation. Mutations act, generally, by perturbing the function of proteins and regulatory processes, and they may do so from the earliest to the latest stages of life.

DNA is not static. Rather, its sequence changes at a slow but measurable rate all the time. Mutations are of central importance to all life forms, including humans. Without mutations, our species would not have evolved over several billion years. Without mutations, individuals would not differ from one another, even within the spectrum that is considered normal. Without mutations, humankind also would not be faced with a myriad of spontaneous abortions, inherited disorders, or cancers. Therefore, we must comprehend both the nature of mutations and the effects they produce.

Chapter 9: Biological Evolution

Biological evolution is the central organizing principle of modern biology and has revolutionized our understanding of life on Earth. It has provided a scientific explanation for why there are so many different kinds of organisms on our planet and how all these organisms became part of a continuous lineage—including humans. DNA is central to understanding biological evolution because all traits in virtually all organisms originate from DNA and are transmitted from generation to generation through it. New mutations in DNA result in the variation of traits that enable the organism to adapt more successfully to its environment. Through increased reproductive fitness, such traits will increase in frequency in a population from one generation to the next, as will the frequency of the DNA changes responsible for them. The process by which genotypes best suited to survive and reproduce in a given environment, and so gradually increase the overall ability of the population to thrive, is called natural selection.

Chapter 10: Human Individuality

Each human being has his or her unique genome. This includes monozygotic twins whose DNA sequences are identical but whose packaging of DNA differs slightly. This genetic uniqueness expresses itself in the form of physical, chemical, and behavioral individuality. In the past, an understanding of this individuality was barely hinted at by the existence of rare, single-gene disorders and by estimating the frequency of polymorphic protein variants in a population of healthy people. As we enter the genomic era, genome-wide studies, including complete DNA sequences on a small but increasing number of people, have already attested to considerable differences in single nucleotide polymorphisms (SNPs), small insertions and deletions, copy number variations (CNVs), and in heterozygosity for rare disease genes. As such studies are conducted on more individuals and groups, they will lead to greater understanding of normal traits and common disorders. Ultimately, this will get us closer to finding out how each of us differs genetically from anyone else.

Chapter 11: Chromosome Abnormalities

The 46 chromosomes found in the nucleus of humans cells—22 pairs of autosomes and one pair of sex chromosomes—are best examined during mitotic