THE HUMAN
GENOME
A USER’S GUIDE
SECOND EDITION



THE HUMAN
GENOME
A USER’S GUIDE
SECOND EDITION

Julia E. Richards
University of Michigan
Ann Arbor, Michigan

R. Scott Hawley
Stowers Institute for Medical Research
Kansas City, Missouri

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04 05 06 07 08 09 9 8 7 6 5 4 3 2 1


To Jesse
and the many unsung heroes

who have helped create modern medicine
through their participation in research



Table of Contents
ACKNOWLEDGMENTS ix
PREFACE

SECTION 1

SECTION 2

SECTION 3

SECTION 4

xi

The Basics of Heredity 1
CHAPTER 1

Slaying Molecular Dragons: Brenda’s Tale 3

CHAPTER 2

The Answer In A Nutshell: Genes, Proteins, and the Basis
of Life 7

CHAPTER 3


Mendel and the Concept of the Gene 15

CHAPTER 4

Human Mendelian Genetics 25

CHAPTER 5

One Man’s Trait Is Another Man’s Disease 37

The Central Dogma of Molecular Biology 45
CHAPTER 6

DNA: The Genetic Alphabet 47

CHAPTER 7

The Central Dogma of Molecular Biology: How Genes
Encode Proteins 55

CHAPTER 8

Splicing the Modular Gene 65

CHAPTER 9

Orchestrating the Human Genome 71

How Chromosomes Move 85

CHAPTER 10

So What are Chromosomes Anyway? 87

CHAPTER 11

How Cells Move Your Genes Around 95

CHAPTER 12

Passing Genes Between Generations 107

CHAPTER 13

The Chromosomal Basis of Heredity 117

Mutation 125
CHAPTER 14

Absent Essentials and Monkey Wrenches

CHAPTER 15

How We Detect Mutations 139

CHAPTER 16

We Are All Mutants 153

CHAPTER 17


What Constitutes Normal? 169

CHAPTER 18

Mutations in Mammoth Genes 177

CHAPTER 19

Expanded Repeat Traits 187

127

vii


viii

TABLE OF CONTENTS

SECTION 5

SECTION 6

SECTION 7

SECTION 8

SECTION 9


Genes, Chromosomes, and Sex 203
CHAPTER 20

The X and Y Chromosomes: The Odd Couple 205

CHAPTER 21

Genetics of Sex, Gender, and Orientation 215

CHAPTER 22

Aneuploidy: When Too Much or Too Little Counts 237

Breaking the Rules 253
CHAPTER 23

Imprinting 255

CHAPTER 24

Imitating Heredity: One Trait, Many Causes 265

The Human Genome Landscape

277

CHAPTER 25

The Human Genome Project 279


CHAPTER 26

There’s Cloning and Then There’s Cloning 287

CHAPTER 27

The Human Genome Sequence

CHAPTER 28

Finding Genes in the Human Genome 311

Complex and Heterogeneous Traits

299

325

CHAPTER 29

Genotype Phenotype Correlations 327

CHAPTER 30

How Complex Can It Get? 337

CHAPTER 31

Quantitative Traits


CHAPTER 32

The MAOA Gene: Is There a Genetic Basis for
Criminality? 353

CHAPTER 33

The Multiple-Hit Hypothesis: The Genetics of Cancer 359

345

Genetic Testing and Therapy 377
CHAPTER 34

Genetic Testing and Screening 379

CHAPTER 35

Magic Bullets: The Potential for Gene Therapy 403

SECTION 10 Fears, Faith, and Fantasies

419

CHAPTER 36

Heroes Among Us 421

CHAPTER 37


Fears, Faith, and Fantasies 429

CREDITS 441
INDEX

451


Acknowledgments
Many people have contributed to the existence of this book, and each of them
has our profound gratitude. We thank our families for their love, patience,
and support throughout the process of writing this book. They are the foundations in our lives that make such endeavors possible.
We especially thank Jeremy Hayhurst, Desiree Marr and Elsevier for giving
us the opportunity to share this book with you. We also thank Catherine Mori,
for her efforts both in the creation of the concept of The Human Genome: A
User’s Guide and for her work on the first edition. That work was a substantial
stepping-stone as we embarked on creating the current version of this book.
Thanks for reading chapters and for many excellent suggestions go to
Beverly Yashar, Paula Sussi, Paul Gelsinger, James Knowles, Jill Robe-Gaus,
Randy Wallach, Rick Guidotti at Positive Exposure, Jerrilyn Ankenman of
NOAH, Julie Porter of the Hereditary Disease Foundation, Linda Selwa,
Marcy MacDonald, Sayoko Moroi, Christina Boulton, Leeann Weidemann
and Alice Domurat Dreger. Thanks go to Carl Marrs and the students in Epidemiology 511, including Miatta Buxton and Gail Agacinski, for reading the
whole book and providing feedback. We also thank the artists who contributed
to this book including Kathy Bayer, Ed Trager, Sophia Tapio and Sean Will
and the artists at Dartmouth Publishing, Inc.
We thank the members of our research groups who have helped in
numerous ways over the years, and we want to express special appreciation
for the efforts of our administrative assistants, Linda Hosman, Nina Kolich,
and Diana Hiebert. Scott Hawley also thanks both the Stowers Institute and

its president, Dr. Bill Neaves, for support and encouragement during the
writing process, and Julia Richards wishes to thank Dr. Paul Lichter for creating an environment in which genetics can bridge the gap between basic
research and clinical practice.
We often use the first person in this book, but when speaking of scientific
findings (“We now know that ...”), we do not mean to lay claim to this vast
body of work we discuss. Many researchers have expended great amounts of
time and energy for more than a century to arrive at the frankly amazing body
of knowledge presented here. Although we are both active researchers in the
field of genetics, in this book we speak as users of the human genome, teachers of genetics, and continual students of this fascinating topic.
We owe thanks to the individuals and families who contributed the stories
in the book, each of which was included not only because it makes some
scientific or educational point but also because these are stories that have
touched our hearts. We want to offer special thanks to Jim Knowles, for letting
us share Brenda’s tale with you, and to Paula Sussi and Paul Gelsinger, who
each continue working in education and policy areas to try to ensure that
what happened to their children Marlaina and Jesse will not happen again.
Others who shared their stories anonymously are just as much deserving of

ix


x

ACKNOWLEDGMENTS

our thanks, even if we must leave them unnamed here. For some of those
stories, we have simplified the tale to keep it focused on the lesson to be
learned from the tale, and in some cases we have changed minor details where
necessary to preserve confidentiality, such as through avoiding use of real
names. In general, where we use no names or only first names, these are still

true stories unless we have indicated otherwise. In rare cases in which we
present a hypothetical situation derived from many similar stories, we try to
indicate that we are doing this by stating that the tale is hypothetical or saying,
“What if we looked at a family with these characteristics?” With many of the
families we encountered the hope that helping other people understand what
has happened will help them cope with the genetic situations in their lives.
We also encountered the hope that the sharing of their tales would keep
someone else from going through the same thing that had happened to their
families. If this book accomplishes that goal for even one family, the writing
will have been well worth all of the effort.


Preface
Huge changes in health care and in our understanding of ourselves will
emerge during the first half of the twenty-first century, and those who take
the time to understand the issues will be in the best position to take advantage of what is to come. If you have picked up this book expecting to find the
biological cousin of the books used in organic chemistry and calculus classes,
you may be surprised by the material that follows. We interweave personal
anecdotes, discussions of ethical issues, historical remarks, and our own opinions right alongside an eclectic mix of scientific facts, molecular models, and
cartoon figures. If you are not a student of the sciences but would really like
to know more about genetics, this book was written with you especially in
mind. It offers all of the fundamental concepts without requiring that you
know anything about hydrogen bonding, hybridization kinetics, or differential equations. Keep in mind as you read that we are all astonishingly complex
organisms and that there are exceptions to almost everything we will tell you
since it is difficult, if not impossible, to arrive at generalizations that can truly
encompass that complexity.
It is not our intention to turn any of you into geneticists, although that
wouldn’t be such a bad thing. Our real hope is to impart enough knowledge
that you will be able to bring this subject into your own lives. It is hoped that
by the end of this book you will know when and why to seek the council of a

medical geneticist or genetic counselor, should you ever need one. It is also
hoped that you will have become sophisticated enough to sort out some of
the myths and misconceptions about human heredity that pass for simple
truths in folklore and in the press. To the extent that we achieve even a small
measure of success with either of these goals, we will consider this book a
success.
Science is often presented as a dry recitation of objective facts so devoid
of opinions and feelings that it is hard to derive a mental image of the author
of the work. In many cases, this objectivity is a good thing. After all, there are
powerful reasons for identifying solid facts and distinguishing them from
opinions. To us, genetics is highly personal and not some abstraction removed
from ourselves, so we have made a point of interjecting ourselves into this
book about the genome that we share with each other and with all of you.
We, authors and readers alike, are the end users of the information in our
own genomes. So join us on a journey through this user’s guide to the human
genome.

xi



Section

THE BASICS OF HEREDITY
This section provides a description of how traits are inherited and introduces
the concept of the gene. We talk about how some of the basic genetic concepts apply to human inheritance and about how patterns of inheritance can
look very different depending on the trait you are studying.

1




SLAYING MOLECULAR
DRAGONS: BRENDA’S
TALE

1

“To dream . . . The impossible dream . . .”
—Don Quixote in Man of La Mancha

Healthy young people aren’t supposed to die. Even amidst the many dangers that arise
from the exuberance and hazards of youth, the death of someone young is always a
shock. And when the blow is delivered from some direction we never expected, were
not waiting for, had never considered, when someone young is felled by an illness such
as leukemia, we are left feeling stunned. It seems impossible to understand such an
outcome, and we find ourselves asking, “How could this have happened?” And the
next question that comes to mind is, “What can be done so that this does not happen
again?”

Brenda Knowles was a graduate student in Scott’s lab back in the late 1980s
(Figure 1.1). She was bright and funny and totally unimpressed by Scott’s supposed seniority. She was trained as a chemist and had begun graduate school
doing biochemistry. However, Brenda had a strong connection to biology and
the organisms that embody so much more complexity than simple biochemistry. Soon she found her way into a lab where there were organisms to work
on, maybe just fruit flies, but organisms nonetheless.
She shared her time in Scott’s lab with the usual array of characters that
populate a “working lab”. Science is a business that cherishes eccentricity, even

FIGURE 1.1 Brenda Brodeur Knowles (1962–1996).


(Photo courtesy of James Knowles.)

3


4

SECTION 1 THE BASICS OF HEREDITY

encourages it. A healthy, growing lab will have its share of unusual characters.
The basic foundation on which any new lab is started is unusual and novel
ideas. Such ideas often come from and attract unusual and novel people.
In some ways, Brenda resembled the classic image of a young scholar. Her
radio played classical music or National Public Radio, drowning out the competing styles of rock music from other desks or that much-ridiculed country
music emanating from Scott’s office. Her desk was neat and her ideas were
equally well organized. She was rigorous in her critical thinking and tenacious
in her pursuit of answers to scientific questions. She wrote (on her own) two
papers from Scott’s lab and went on to continue her scientific training by
taking on a postdoctoral fellowship at Yale.
On her way to that fellowship, she married a handsome young doctor and
they bought a beautiful little house in rural Connecticut. If you sense a fairy
tale being told here, there’s a reason: Brenda’s life always seemed a bit of a
fairy tale to Scott. This fairy tale was unusual only in the sense that Brenda
was enough of a feminist to slay most of her own dragons.
That is, until Brenda got sick. Sometime in the early 1990s, Brenda
acquired acute myelogenous leukemia (AML). We’ll talk more about
leukemia later in this book. The disease results from a rather nasty genetic
alteration that occurs in one of the stem cells that produce the circulating
cells in our blood. The result is an instruction for the altered stem cell to
divide repeatedly. Leukemia was the ultimate dragon in Brenda’s life, and she

committed all of her resources to slaying it. She tried everything that was available, or even close to available. She suffered more than our words can convey.
In the end, she lost the battle.
The battle she lost was just one battle in what the press often refers to as
the “war on cancer”. In 1969 a full-page ad in the New York Times urged President Nixon to begin a war on cancer, saying “. . . We are so close to a cure
for cancer. We lack only the will and the kind of money and comprehensive
planning that went into putting a man on the moon.” The war on cancer was
proposed in 1969. Brenda lost her battle with cancer in 1996.
There have been too many such battles. For most of history the idea of a
cure for cancer has seemed like an impossible dream. We daresay that there
will not be a single reader of this book who does not know someone touched
by cancer. After all, one in four of us will get cancer in our lifetimes. But
not all the battles are lost. There are some cures, many remissions, and many
cases in which the cancer is simply held in check for years at a time. Still,
Brenda died.
With impatient excitement, we watch advances in cancer treatment begin
building on the results coming out of genetic studies of cancer. Breakthroughs
in understanding of the molecular mechanisms of various forms of leukemia
have led to breakthroughs in the development of new treatment approaches.
Scientists have begun creating molecular “lances” aimed at slaying the monsters that are the various kinds of leukemia. Their molecular lances are drugs
designed based on an understanding of what has gone wrong at the molecular level in the leukemia cells. How wonderful that these weapons against
leukemia are emerging; how terrible that they will come too late for Brenda.
Increasingly, we are seeing “magic bullets” emerge based on breakthroughs
in our understanding of the underlying mechanisms of diseases caused by
defects in genes. Some of these new cures use gene therapy, but we are going


CHAPTER 1: Slaying Molecular Dragons: Brenda’s Tale

5


to see a lot of other pharmaceutical treatments emerge that will not use gene
therapy even though they will be based on the information gained from the
study of genes.
In a very real sense the scientists who are developing these new genetically based anti-cancer drugs are having to decipher a “lock” smaller than a
thousandth of a pinpoint. That lock had been created by a change in the
genes of a human cell. That lock committed that cell to a future of unrelenting cell division. The cure comes from building a “key” that releases that
lock. If you understand that metaphor, that’s wonderful. It would be even
better if you understood the “magic bullet” and the “dragon-slaying”
metaphors that we used before.
But we hope, we really hope, that you find such trite metaphors to be
entirely unsatisfying. We hope you want to know what we mean by cells, and
genes, in order to understand what all of these metaphors really mean.
Because the scientist who builds this “magic bullet” isn’t a wizard or a magician, he or she is a biologist. And as much magic as we biologists do see in
the living world, we need to describe living systems, and manipulate them, in
terms of molecules that interact with and within structures called cells.
That need to describe the chemistry of molecules and the structures of
cells has been interpreted by others as a need to use terminology that requires
a bachelor’s degree in biology (and, better yet, chemistry!) to comprehend.
However, we think that we can keep the chemistry in hand, by focusing on
the processes that go on in a cell and on the functions that certain types of
molecules play in the cell. We don’t need to understand polymer chemistry
to play with Legos made of plastic polymers. Similarly, to understand molecular genetic processes, we need only to know what overall structure the cell is
trying to build, what pieces we have in our toy box, and how to snap them
together. This does not mean that the chemical terms and structures are
unimportant. Such details are in fact critical to anyone who is going to carry
out studies of these systems. However, a lot of the concepts unveiled by such
studies can then be understood without needing the expertise that was
required to make the discovery in the first place.
Using that kind of framework, we will build you the verbal equivalent of
Lego models of cells and, more importantly, of genes. We’ll try to show you

how genes work and how they control the activity of the cell. In time, we’ll
build a model of an “engine” that controls when cells divide and describe the
“lock” that forces that engine to be locked “on.” And we’ll tell you how
scientists are finding keys that disarm some of the locks that commit cells to
relentless division and growth.
Treatments for leukemia are just one such example of the kinds of
“genetic” medicines that will emerge with increasing frequency in the future.
There will be ever so many more. The sad news is that the “cure” will have
come too late for Brenda; the good news is that it will come at all! There will
be more Brendas, but now we can dream the impossible dream, that there
will be cures and the outcome will be better. Much better.



THE ANSWER IN A
NUT SHELL: GENES,
PROTEINS, AND THE
BASIS OF LIFE

2

There are always those who ask, what is it all about? For those
who need to ask, for those who need points sharply made, who
need to know “where it’s at,” this:
—Harlan Ellison1
Our genes provide a blueprint for our bodies. In doing so they set
some upper and lower limits on our potential. Our interaction
with the world and others defines the rest.
—R. Scott Hawley


Marlaina Susi was a beautiful little eight-year-old girl who was active and friendly. She
was an energetic child who was filled with a love of life and embraced everyone she
encountered. She earned above average grades, participated in a variety of sports and
other activities, and had not missed a single day of school due to illness during the previous school year. She has also been described as a picky eater, but no one realized at
the time that her aversion to dietary protein might have
been protecting her by helping her avoid high levels of
protein that could be harmful to people with some
types of metabolic defects. In 1999 her happy and
seemingly healthy life was interrupted one day by a
brief illness and fever from which she should have
recovered, as young children normally recover from the
usual array of “bugs” that get passed around an elementary school. Instead of recovering and rejoining
her friends at school, she developed elevated levels of
ammonia in her blood, was hospitalized, and died
thirty three days later. After her death, her grief-stricken
family continued their search for an answer to what had
caused her death. They were told that she had a defect
in the ornithine transcarbamylase (OTC) gene, one of
several genes responsible for helping our bodies cope
with the ammonia (NH3) that forms as a normal part of
Marlaina Susi (1991–1999)
metabolizing protein that we consume. If her OTC
(Photo courtesy of the Susi family)
defect had been diagnosed during her hospital stay,
there were medical remedies that would have been
available to help her. But getting a correct diagnosis on time was complicated by several
things: OTC defects are rare, they usually manifest in infants, they are usually seen in
boys rather than girls, and Marlaina’s defect was partial rather than complete. So what
is an OTC defect, how can it have such a devastating effect, and why did the problem
not show up until Marlaina was eight years old? To understand what happened to

Marlaina, and to eventually find ways to protect other children with similar gene
defects, we need to understand how a defect in a gene can lead to such devastating
consequences.2
1

From “Repent Harlequin!” Said the Ticktockman by Harlen Ellison.
On the web site for the National Urea Cycle Disorders Foundation (NUCDF), there is a page
that talks about Marlaina and the two memorial marches that have been held in her name to
raise money for the Foundation. Information on OTC and other urea cycle disorders can be
obtained from NUCDF, the Canadian Society for Metabolic Disease, or the National Organization for Rare Disorders.
2

7


8

SECTION 1 THE BASICS OF HEREDITY

THE BLUEPRINT INSIDE EACH CELL
Our bodies contain billions of cells, intricate little factories that carry out their
own internal functions, as well as carrying on complex interactions with surrounding cells and the rest of the body. Almost all of those cells have a nucleus
that contains most of the information required to make a complete human
being (Figure 2.2). We refer to this set of information contained in the
nucleus as our genome. It is composed of a chemical called deoxyribonucleic
acid (DNA). Our genome doesn’t function as a single entity but rather is comprised of tens of thousands of subunits of information called genes.

FIGURE 2.1 A microscopic view shows that a cell is a sack-like structure made of a
membrane filled with cytoplasm in which structures called organelles are suspended.
The largest organelle, the nucleus, contains the information used to run the cell and

produce its structures. Actively growing cells contain a large inclusion within the
nucleus called the nucleolus, the source of information used to construct ribosomes.
Outside of the nucleus in the cytoplasm, millions of ribosomes use genetic information
received from the nucleus to produce proteins. The endoplasmic reticulum and the
Golgi apparatus are folded membrane structures where proteins may get additional
chemical modifications and where key steps direct proteins to their final destinations.
Thousands of mitochondria produce energy to run the cell. Membrane-bound containers called lysosomes hold molecules whose specialized functions need to be kept
separated from the cytoplasm, like proteins that digest other kinds of molecules. This
picture does not show all of the organelles in the cell or even all of the types of
organelles in a cell, but it does show samples of organelles of importance to things we
talk about in this book. How many of which organelles are present can vary for different cell types and different situations such as very active cell growth. The key concept
here is that the genetic information is located inside of the nucleus and the ribosomes
that will “read” that information are located outside of the nucleus. (Courtesy of Edward H.
Trager.)


CHAPTER 2: The Answer in a Nut Shell

9

Virtually all of the cells in our bodies contain exactly the same full set of
genes. Genes themselves are little more than repositories of information that
tell the cell how to produce a gene product that carries out an essential function. Most often gene products are large, complex chemicals called proteins
that actually do the work for and provide the structure of our cells. Proteins
are the business end of cellular processes. The cell uses some proteins, such
as tubulin, keratin, and collagen, as structural pieces of scaffolds and skeletons that are both inside and outside of cells. Other proteins called enzymes
carry out a host of essential biochemical reactions, such as digestion and
energy production.
You see colors and detect smells because of receptor proteins such as
color opsins and odor receptors. Your heart or skeletal muscles move because

of proteins called actin and myosin. Your body fights off infection with the
help of proteins called immunoglobulins. Thus, our cells differ in size and
shape. They carry out different functions such as transmitting pain signals or
producing stomach acids because of the differences in the proteins they
produce. In fact, one type of cell may even make different proteins at different points in the life span of a human being.
Many, if not most, of the differences that exist between us reflect the fact
that the information in a gene can be permanently altered by a process called
mutation, and changing the information in a gene by mutation changes the
protein product that it creates. Although many think of mutation as a term
for something negative or harmful that can cause birth defects and genetic
disease, mutations can also be neutral (having no detectable effect) or even
beneficial. They can cause differences in many of the characteristics by which
we recognize each other: height and build; hair color and texture; and shapes
of face, nose, ears, eyes, and eyebrows. Mutations can affect things that are
harder to define, such as behavior. Mutations are responsible for differences
that are very important even if they are invisible to us on a daily basis, such
as blood type. Without mutations, we would all have exactly the same set of
genetic information and billions of us would all resemble each other in much
the same way that identical twins resemble each other. The vision of billions
of identical humans is a chilling thought that leaves us quite pleased with the
amount of diversity we see around us.
The term mutation refers to a startlingly large array of different types
of processes that can permanently change the structure, and thus the information content, of genes. Although mutation occurs rarely, there are an awful
lot of us, we breed well, and we have been breeding for a very long time. Thus
there has been ample opportunity for mutations in each of our genes to occur
and in many cases to be spread widely throughout our population. These
altered genes may produce an altered protein or produce no protein at
all. Although missing proteins often turn out to cause severe or even lethal
phenotypes, altered proteins may cause a broad range of phenotypes, in some
cases severe and in other cases almost undetectable. Mutations that result in

altered proteins are responsible for much of the diversity we see around us.
Accordingly, genes affect our form, appearance, physical abilities and limitations, talents, and many aspects of our behavior as well. Each of us received
one complete copy of the “human genome” from our mom and one copy
from our dad. Thus each of us carries two copies of each gene. When we make
gametes (sperm or eggs), we place only one of our two copies of each gene


10

SECTION 1 THE BASICS OF HEREDITY

in each gamete. This trick sees to it that each generation will always have two
copies of each gene, and it introduces an amusing bit of randomness to the
process. Each sperm or egg that we produce consists of a different combination of genes derived from our own mothers and fathers. However, when we
pass genes along to the next generation, some of the genes we pass along are
the copy we got from mom, and for other genes we pass along the copy that
we got from dad. Thus each new baby is the result of implementing a set of
genetic instructions created by two rolls of the genetic dice, one that took
place in the father and one that took place in the mother.
Genetic diseases, or inborn errors, result from cases in which the DNA
blueprint is incorrect or incomplete, usually because a specific gene is
damaged or missing. In such a case, the cells of an individual bearing such a
genetic defect will make a damaged version of that protein or perhaps not
make the protein at all. For example, people like Scott who lack functional
copies of a gene that makes one of the color opsins will be unable to distinguish colors. So genetic disorders are not always lethal, and may not even
make you sick. Many differences between copies of the genome present in
different people cause no harm at all. In some cases they may cause simple
cosmetic differences. In other very rare cases, they may even give someone a
desirable characteristic not shared by their neighbors, such as resistance to
an infectious disease. All too often, though, differences in the genetic blueprint are not just neutral changes; they are considered defects because they

cause a problem.

A DEFECT IN THE OTC GENE CAUSES ALTERED PROTEIN METABOLISM
To look at how defects in the genetic blueprint borne, by a developing zygote
result in loss of an essential function in the body, lets look at a serious gene
defect that is sometimes found in the human genetic blueprint. Many harmless biochemicals that make up our bodies can become harmful if we have
too little or too much of them. Examples include blood sugar, cholesterol and
nitrogen.
Normally, nitrogen levels in our bodies are regulated by a set of biochemical reactions called the urea cycle, the process by which our bodies
convert excess nitrogen from food into a compound that can be excreted
from the body (Box 2.1). A protein called ornithine transcarbamylase, or
OTC, carries out one of the critical steps in the urea cycle.
Babies who are born with a defect in their genetic blueprint at the point
that contains the information needed to make the OTC protein cannot properly control ammonia levels in their blood because they don’t correctly metabolize proteins from their food (Figure 2.2). If there is no OTC protein, excess
nitrogen does not get carried through the urea cycle the way it should. One
consequence is that excess ammonia accumulates, and the ammonia is toxic.
When a baby is born who is completely lacking in functional OTC protein,
symptoms within the first three days of life may start with problems with
breathing and eating. If these babies are not treated, ammonia levels build
up in their blood and their brain, they go into a coma, and they die. Other
children like Marlaina, with a partial defect in which OTC levels are reduced
but not gone, may live healthy lives for years because the small amount of


CHAPTER 2: The Answer in a Nut Shell

BOX 2.1

11


DEFECTS IN THE UREA CYCLE

When we eat protein, nitrogen enters the body. The body uses some of the
nitrogen but some of it needs to be eliminated. The protein ornithine transcarbamylase carries out one of several critical steps in the urea cycle. In babies
with a normal copy of the gene that makes the OTC protein, the urea cycle
uses dietary nitrogen to produce urea and the extra nitrogen from the diet is
thus excreted. A baby who has only damaged information for making OTC
protein cannot use the urea cycle to turn nitrogen into urea to be excreted.
These babies have problems that include accumulation of nitrogen-containing
ammonia, which can be toxic. Excess ammonia can lead to problems such as
brain damage, liver damage, coma and even death. How severe the problems
are depends on whether the OTC protein is completely missing or whether the
protein is damaged but still able to carry out its job at a low level. Defects in
genes controlling the other steps in the urea cycle can cause similarly terrible
consequences. Children with genetic defects affecting other steps in the urea
cycle may not all have identical health problems, but one of the common problems for urea cycle disorders is the build up of ammonia. Diets and treatments
exist that can help limit build-up of ammonia, but there is no cure and the
treatments themselves are difficult and limited in how much they can help.
According to the National Urea Cycle Disorders Foundation, 1 in 10,000 children are born with a urea cycle disorder, and some cases of Sudden Infant
Death Syndrome may actually be undiagnosed urea cycle disorder cases. Many
children with urea cycle disorders are seriously harmed within days of birth,
and many more die before their fifth birthdays. More information about urea
cycle disorders and prenatal screening can be obtained from the National Urea
Cycle Disorders Foundation.

OTC activity in their bodies is enough to handle the very small amounts of
nitrogen coming in from their low-protein diet. Thus, they might live a long
time without being diagnosed until an illness or consumption of too much
protein causes a crisis that requires prompt diagnosis and treatment to
survive. All too often, in these later onset cases, the need for treatment during

a crisis is urgent and great harm can occur during any delay while doctors
carry out tests and struggle to sort out a diagnosis that can be difficult to
make.
One fundamental point must be made here: the altered information in
the damaged OTC gene does not directly do any harm or cause the disease.
Rather the disease results because the child lacks intact, functional OTC
protein needed to carry out an essential function. Although the primary event
in the disease may be the damaged gene, the direct cause of harm is in the
failure of the gene product produced by that gene. A damaged gene, like
the blueprint for a cruise missile, is in and of itself pretty harmless. It is the
product of that blueprint (either the cruise missile or the defective or absent
protein) that poses a problem.


12

SECTION 1 THE BASICS OF HEREDITY
Nitrogen in
dietary protein
turns into
toxic ammonia

No OTC
protein

OTC
protein

“Broken” urea
cycle


Normal urea
cycle

Excess ammonia
accumulates

Ammonia turns
to urea

Ammonia can’t be excreted,
builds up to cause liver damage,
brain damage, coma or death

Urea is excreted, which removes
excess nitrgen from the body
and keeps the baby healthy

FIGURE 2.2 If there is a defect in the part of the genetic blueprint responsible for the
ornithine transcarbamylase protein (OTC), the consequences can be a serious illness
that can lead to death if toxic levels of ammonia are not controlled. The different diseases of the urea cycle are complex and accumulation of ammonia is only part of the
problem, but we show it here because it is a central key to the problem.

THE ANSWER IN A NUTSHELL
So this is our answer in a nutshell: Usually, no one dies because of a defect in his
or her genes; they die because that genetic defect alters the gene product so that it no
longer performs its function correctly. This is the foundation for everything else
we will discuss—that information, in the form of DNA located in the nucleus,
directs the production of gene products (which are mostly proteins) that actually carry out the cell’s functions. And many differences we find between different human beings trace back to a change in how some function was carried
out (or not carried out at all) by a damaged (or missing) gene product. There

are in fact exceptions to this generalization, as there are exceptions to almost
everything we will tell you about in this book, but keeping this core concept
will give you a framework for everything else we will say.
In the case of Marlaina, we see that her death was the result of a defect
in her genetic blue print at the point that contained the information needed
to make a functional OTC protein. We also see that in her case the defect
ended up with her having reduced levels of OTC activity rather than a complete absence of OTC activity. This explains why she managed to remain
healthy through the eating habits that kept her protein intake low. Much