Susceptible? , focus students’ attention on the practical, medical applications
of understanding human genetic variation at a molecular level. Lesson 3
looks at treatment options that become possible with the discovery and
sequencing of a disease-related gene. In contrast, Lesson 4 focuses on the
likelihood that genetic testing for common, multifactorial diseases will
increase in the future and invites students to consider the prospects that
this information will help individuals make wise decisions about their
personal health. Specifically, Lesson 4 uses heart disease as an example
of the common, multifactorial diseases that constitute the bulk of the
healthcare burden in the United States and other developed countries.
The lesson builds on the treatment of variation in the previous lessons
and sets up the discussion of ethics that is central to Lesson 5, which
deals with genetics and cancer.
For the most part, the treatment of genetics in high school focuses on single-
gene traits. In addition, most of the single-gene traits discussed are disorders,
because they provide reasonably straightforward examples of Mendelian
patterns of inheritance. Research in human genetics, however, increasingly
addresses multifactorial traits, that is, traits that result from the interaction
of multiple genes and environmental factors. Among the multifactorial
traits that come most quickly to mind are behavioral characteristics that
are controversial and that often attract media attention—for example,
intelligence, sexual preference, aggression, and basic personality traits such
as novelty-seeking behavior or shyness. Research into the relative genetic
and environmental contributions to behavioral traits has been uneven and
is confounded by the difficulty of defining and measuring the phenotypes
in question with any degree of accuracy and reliability.
A more productive area of active investigation involves the multifactorial
diseases that are among the leading causes of sickness and death in
developed countries—for example, heart disease, cancer, diabetes, and
even psychiatric disorders such as schizophrenia and bipolar disorder
(manic-depressive illness). Research has already uncovered genetic
markers, and in some cases specific genes, that are associated with the
development of these maladies; more genetic associations are sure to
emerge as research into human genetic variation expands.
The identification of more genetic associations raises the virtual certainty
of genetic testing for common, multifactorial diseases. Genetic testing
is not a new phenomenon; it is done routinely to determine the risk for
or presence of a number of single-gene disorders, including examples of
Mendelian inheritance in the high school curriculum: Tay-Sachs disease,
cystic fibrosis (CF), Huntington disease, phenylketonuria (PKU), and
Duchenne muscular dystrophy. The predictive power of these tests lies
in their technical reliability and the direct connection between gene and
phenotype. Although there is considerable variation in symptomology for
many single-gene disorders, the presence of the gene (or genes) does result
in the generally recognized phenotype.
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Our knowledge of the biological relationship between gene and phenotype
is much less certain for multifactorial diseases. It is clear, for example,
that genetic factors contribute to the risk for early onset heart disease, but
the exact relationship is as yet unclear, as is the case for the relationship
between certain genetic markers and the risk of schizophrenia. In these
cases, the distance between gene—or genes—and phenotype is greater than
it is in single-gene disorders, probably because of a host of environmental
variables whose influences on phenotype are difficult to discern.
Genetic testing for common, multifactorial diseases will affect more people
than does testing for relatively rare, single-gene disorders. Many of the same
ethical and policy questions will apply—privacy and confidentiality, for
example—but the uncertainty inherent in genetic testing for multifactorial
diseases will introduce some new challenges for the public, chief among
them the notions of susceptibility and risk. You may learn from a “positive”
test that you are susceptible to developing the disease in question, but
that will not mean that you are destined to develop the disease. Nor will
a “negative” test mean that you definitely will not develop the disease. In
addition, while you may learn that there is an increased relative risk of
developing a given disease—that is, a risk that is increased above the risk
for the general population—the absolute risk may still be quite low.
It is likely that a deeper understanding of both the molecular basis of
common, multifactorial diseases and the advent of genetic testing for these
diseases will improve the climate for the development of more focused
clinical interventions and for preventive medicine. Multifactorial diseases
tend to develop later in life than do single-gene disorders, which generally
exact their toll in infancy, childhood, or adolescence. There is, therefore,
more opportunity to ameliorate the effects of multifactorial diseases
through a combination of medication and environmental modification.
That, of course, requires a partnership between patients and healthcare
providers to identify and modify the environmental variables that magnify
one’s genetic risks. That is the ultimate message of this lesson.
Web-Based Activities
In Advance
None.
Materials and Preparation
Photocopies and Transparencies
Equipment and Materials
• 1 copy of Master 4.1 for each student
• Dice (1 die per group of
• 1 copy of Master 4.2 for each student
3 students)
• Copies of Masters 4.3–4.6, cut up and
• Relevant-genes envelopes
put into envelopes
(1 envelope per student)
To make a classroom set of relevant genes envelopes, first make as many
copies of Masters 4.3–4.6 as you need to provide one-fourth of your class with
the genetic risk indicated on each master. To minimize copying, each master
contains four of the same statements. Insert one statement into each envelope
and label the envelope “Relevant Genes.”
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Student Lesson 4
Human Genetic Variation
1. Begin the lesson by asking students to suggest definitions of the term
Procedure
“risk.” You might prompt the discussion by asking students to think
about risky behaviors that are a part of adolescence. Write three or
four of the definitions on the board.
Students may suggest that “risk” refers to the chance that something
bad or negative will happen, as, for example, the risk involved with
dangerous behaviors. Help students see that one way to think about
risk is in terms of one’s chance of experiencing a particular event.
For example, if a person performs aerial acrobatics on skis, he or
she has some risk of getting hurt.
2. Ask students whether they think risks can be modified. For example,
ask them if there is any way they can modify their risk of being
robbed or their risk of a heart attack or of getting cancer.
Answers will vary.
3. Read the following story to the students:
Death of an Olympic Champion
Ekaterina Gordeeva and Sergei Grinkov, young Russian
figure skaters, had won two Olympic gold medals in
the pairs competition and were expected to continue
dazzling audiences and judges for years into the future.
In November 1995, however, 28-year-old Sergei suddenly
collapsed and died during a practice session. He was a
nonsmoker, he was physically fit, and there had been
no warning signs. What happened to cause this young
athlete’s early death?
Source: Courtesy of Sinauer Associates, Inc., from E.P. Mange and A.P.
Mange: Basic Human Genetics, Second Edition , 1999.
4. Explain that Sergei Grinkov was born with a mutation called PL(A2)
in a single gene that affects the formation of blood clots. The mutation
causes clots to form in the wrong places at the wrong time. If such
a clot forms in one of the arteries that supply the heart, a heart
attack can result. Ask students to consider whether this mutant
allele influenced Sergei Grinkov’s risk of a premature heart attack.
The mutant allele increased Grinkov’s risk of premature heart attack
relative to the risk for the general population. Relative risk is the risk
for any given person (or group) when considered in relation to the rest
100
of the population. One may have an elevated relative risk but still have
a low absolute risk. For example, one may have an increased risk of 20
percent above the risk for the general population, but may still only
have a 5 percent risk of suffering the disease in question by, say, age 50.
5. Ask the class to suggest ways that Sergei Grinkov could have modified
his behavior had he known he was at increased risk for premature
heart attack.
Given that this single-gene disorder affects the clotting process, it
likely would have been difficult to reduce the risk of heart attack
by modifying the environment. There is some indication that the
PL(A2) mutation can interact negatively with increased cholesterol
concentrations in the blood, or levels. If, for example, plaques formed
by excess cholesterol break off from the lining of a coronary artery and
create a lesion in a blood vessel, the PL(A2) mutation can cause the
formation of a clot that impedes blood flow, resulting in a heart attack.
Maintaining low cholesterol levels through diet and exercise might thus
reduce the risk of premature heart attack for a person who carries the
PL(A2) mutation.
6. Explain that premature heart attacks resulting from single-gene
disorders are uncommon. Most heart attacks occur later in life and
result from a combination of genetic and environmental factors that
produce atherosclerosis, the buildup of cholesterol deposits in the
arteries. In this lesson, students will have an opportunity to explore
the idea of medical risk and learn how genetic analysis is helping us
understand and define people’s risks in new ways.
7. Give each student one copy of Master 4.1, Rolling the Dice, and direct students to work in groups of three to play the game described.
Give the students about 10 minutes to finish the game.
8. Ask how many students suffered a fatal heart attack. Determine
at which life stages the heart attacks occurred, and record this
information on the board.
9. Ask students how the game is and is not like real life.
The game is like real life in that life expectancy depends on many
risk factors. The game is not like real life because students rolled the
die to determine what their risk factors would be instead of making
personal choices. The game also involved only environmental risk
factors, not genetic ones. If students fail to mention that the game
does not address genetic risk factors, try to elicit that response by
asking about Sergei Grinkov.
101
Student Lesson 4
Human Genetic Variation
10. Acknowledge the importance of considering genetic risk factors in
the development of heart disease, and ask students what effect(s)
factoring this information into the game might have.
Answers will vary. Because of the example of Sergei Grinkov and
because of their own sense that sometimes heart disease tends to
“run in families,” students may think that including genetic factors
This part of the game is
in the game will inevitably have a negative effect. You may choose
futuristic. At this time, we
to point out that for some people, the effect might be positive, or
either do not have the
let students discover this in Step 11.
technology to determine
each person’s individual
11. Give each student one relevant-genes envelope and explain that this
risk or, if the technology is
envelope contains information about his or her genetic risk for a fatal
available, conducting such
heart attack. Ask students to open the envelopes and share their
heart points until you have addressed all four values: –10, 0, +10, +40.
genetic testing is not yet a
Point out that the genetic risk falls off rapidly as genetic relatedness
regular part of medical
decreases, from 40 points for first-degree relatives to no points for
care. Nevertheless, you
third-degree relatives. Explain that this is the case generally for
may wish to point out to
multifactorial diseases.
students that with the
rapid pace of our progress
12. Give one copy of Master 4.2, Thinking About the Game, to each student, and ask students to complete the master to compare the results of the
in understanding the
game with and without considering genetic factors.
molecular basis for
disease, such testing may
13. Conclude the lesson by inviting each group to offer its answer to one
well be in their future.
of the questions on Master 4.2. Then, invite other groups to contribute
additional insights or information or to challenge ideas expressed by
other groups.
Question 3. Remember, if you exceeded 85 points in any life stage, you
have had a fatal heart attack. What effect did including your points for
You may wish to collect
genetic risk have on your outcome?
Master 4.2 to evaluate
Answers will vary. Including the genetic data may have pushed some
how well students
students over the threshold to a heart attack. Others may have escaped
understand the
a heart attack because of the protective effects of their genes, while still
issues involved.
others may have experienced no change. The important point is that
the environmental risks—the choices they made—have been played out
against a genetic background, which differs for each person.
Question 4. Think about the choices you made in each life stage.
a. Did everyone make the same choices?
No, each person made somewhat different choices.
b. Were all of the choices equally risky?
No, some of the choices carried greater risks than others, and some
decreased the risks.
102
c. Were the risk factors associated with the choices reversible?
Most of the risk factors were reversible—smoking, exercise, and
stress, for example.
d. Were the choices under personal control?
In the game, choices were made on the basis of a roll of a die.
In life, however, most of these choices are under personal control.
Question 5. Now, think about the effects of genetic risk factors in
each life stage.
a. Does everyone have the same genes?
No, each person (except identical twins) has different genes.
b. Did all of the genetic factors have the same effect?
No, some genetic factors had negative effects, some were neutral, and
some provided protection.
c. Were the genetic factors reversible or under personal control?
We cannot change the genes with which we are born. We can,
however, sometimes modify the effects of those genes by modifying
the environment—for example, by changing some of our behaviors.
Question 6. Assume that genetic testing showed that you were at
increased risk for a fatal heart attack 20 years from now. Would you
want to know? Why or why not? Would that information cause you to
change your behavior? If not, what kind of information or event would
cause you to change your behavior?
Answers will vary, but the assumption is that knowledge of increased
genetic risk would cause one to modify his or her behavior to reduce
the environmental risk factors. A very important point here is that a
family history of heart disease is usually an indication of increased
genetic risk, even if we are not yet able to identify predisposing genes
and attach some risk figure to them. The literature on health and
behavior—and personal experience—demonstrates that people do not
always change their behaviors in the face of well-documented risk.
Cigarette smoking is perhaps the classic example that applies well to
adolescents. Some people will not change their behavior even in the face
of serious illness.
103
Student Lesson 4
Human Genetic Variation
Question 7. We know about only a few genes that affect the likelihood of
a heart attack, and we have the ability to test for even fewer of them. In
the future, we certainly will learn about more of these genes. How will
increased knowledge of the genetic factors associated with heart disease
have a positive impact on individuals and society? How will it have a
negative impact?
Increased knowledge about such genes will lead to increased testing
and the development of new clinical interventions. Our ability to test
for genes that predispose to heart disease will mean that we can detect
those genetic susceptibilities sooner and act on them more quickly—
for example, with drugs targeted at the specific biochemical defects
involved and by modifying risky behaviors.
The frequency of heart disease, and other common, multifactorial
diseases, means that genetic testing will be applied to many more
individuals than are tested now, with attendant concerns about
how we use the results of the testing. In addition, genetic testing
for multifactorial diseases will require education of the public
and healthcare providers about the meaning of susceptibility
and predisposition. Lesson 5 explores some of these issues in
more detail.
Question 8. Our ability to detect genetic variations that are related to
common diseases will likely improve. How might that ability shift some
of the responsibility for health care from physicians to individuals?
This question is designed
If we know that we are at increased genetic risk for a particular disease,
to draw students’
we can try to avoid environmental factors, such as risky behaviors,
attention back to the
that increase the risk further. Many healthcare professionals think that
lesson’s major concept.
increased understanding of genetic variation will provide an important
impetus to preventive medicine. Prevention will require a close
partnership between healthcare providers and consumers. Healthcare
specialists may be able to provide us with tests to uncover our genetic
predispositions, but it will be up to each one of us to avoid increasing
those risks by engaging in high-risk behaviors.
In short, each of us will have to assume more responsibility for our
own health. This requires active participation by the individual and
is very different from the prevailing model, which is based not on
prevention but on treatment after the disease occurs. In the current
model, the individual (the patient) is generally a rather passive
recipient of health care.
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Lesson 4 Organizer
Procedure
What the Teacher Does
Reference
Ask students to suggest definitions for the term “risk.” Ask students
Page 100
to think about risky behaviors that are part of adolescence. Write
Step 1
several definitions on the board.
Ask students whether they think risks can be modified.
Page 100
Step 2
Read aloud the story on page 100, “Death of an Olympic Champion.”
Page 100
Step 3
Explain that Grinkov was born with a mutation called PL(A2) in a
Page 100
single gene that affects the formation of blood clots. The mutation
Step 4
causes clots to form in the wrong places at the wrong time. If such
a clot forms in one of the arteries that supply the heart, a heart
attack can result. Ask students to consider whether this mutant allele
influenced Grinkov’s risk of a heart attack.
Ask the class to suggest ways that Grinkov could have modified his
Page 101
behavior if he had known he was at increased risk for premature
Step 5
heart attack.
Explain that premature heart attacks resulting from single-gene
Page 101
disorders are uncommon. Most heart attacks occur later in life and
Step 6
result from a combination of genetic and environmental factors.
Tell students that they will now explore medical risk and learn how
genetic analysis is helping us understand and define risk in new ways.
Give each student a copy of Master 4.1. Have students work in groups Page 101
of three to play the game.
Step 7
Ask how many students suffered a fatal heart attack. Record on the
Page 101
board the life stages at which the heart attacks occurred.
Step 8
Ask students how the game is and is not like real life.
Page 101
Step 9
Acknowledge the importance of genetic risk factors in the
Page 102
development of heart disease.