Medical Biochemistry

Dr. Menon
CVC 2925
February 22, 2011

Solving Genetics Problems

For your convenience, the practice problems available on the web are also repeated at the
end of this handout. The explanations for the answers are only available from the web.

Table of Contents

Lecture objectives ............................................................................................................................2

Key concepts ....................................................................................................................................2

The basics of solving genetics problems .........................................................................................3

X-linked Traits .................................................................................................................................6

Population Genetics .........................................................................................................................6

Sample Questions...........................................................................................................................10

Answers to the problems................................................................................................................14

Index ..............................................................................................................................................15

1
 The lecture objectives are:

1. To solve problems based on Mendelian transmission of alleles in pedigrees.

2. To solve problems in population genetics based on the Hardy-Weinberg Equation (p2 +

2pq + q2 = 1).

The key concepts to understand are:

1. Mendel’s laws state that genes segregate independently. Segregation of alleles is

therefore a mutually exclusive event. This means that loci on different chromosomes are
inherited independently.

2. The probability that BOTH of two mutually exclusive events will occur is equal to the
probability that the first event will occur multiplied by the probability that the second
event will occur. This is known as the product rule.

3. The probability that EITHER of two mutually exclusive events will occur is equal to the
probability that the first event will occur plus the probability that the second event will
occur. This is known as the sum rule.

4. Most Mendelian inheritance problems can be solved using a three step approach. First,
draw the pedigree; second, draw the alleles being transmitted; and third, choose the
appropriate rule, product or sum, in order to compute the correct answer.

5. When solving problems involving population genetics, the Hardy-Weinberg equation is

used (p2 + 2pq + q2 = 1), where p2 is equal to the normal, or wild type frequency of an
allele within the population, 2pq is equal to the carrier frequency within a population, and
q2 is equal to the frequency of affected individuals (homozygous for the allele) within the
population.

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 The basics of solving genetics problems

Statisticians have devised many different methods for approaching the same problems, so
we have chosen the more “simple” approach that gives reasonably accurate answers and which
we think reflects the level of questions that we have seen on the board exams. In research studies
one can solve these problems with higher numerical accuracy using Bayesian statistics - a
method of analysis that incorporates prior knowledge (for example, on prior presence of affected
children), specifications of prior distributions and accumulated clinical data experience into
making probability calculations and designing future clinical trials. For students interested in
further reading on these methods we have made available recent review papers (on Blackboard).

Solving genetics problems is similar in many ways to calculating probabilities of flipping

a "run" of heads or tails on a given coin. For instance, the odds of flipping a coin heads once,
obviously, is one in two; the odds of flipping heads twice in a row is one in four (one in two
multiplied by one in two). In genetics, this is known as the product rule-the probability that two
mutually exclusive events will both occur. The product rule states that for a given probability A
and probability B, the odds that both will happen is A x B (0.5 x 0.5 = 0.25). You will use the
product rule often when solving genetics problems, especially when you want to calculate, say,
the odds that a grandchild will carry a given allele that the grandparent carries.

You may want to learn something different, however. For instance, if you flip a coin
twice, what are the odds that it will come up heads just once? To answer this, you use the sum
rule, which measures the probability that either of two mutually exclusive events will occur. The
sum rule states that for a given probability A and probability B, the odds that either will happen
is A + B. But be careful here: the "A" and "B" in this instance does not have the same
numerical value as that in the above paragraph. Probability "A" in this case would mean the
chance that the first flip came out heads and the second didn't (remember, we want to know the
odds of it landing heads only once). So "A" is equal to the odds of it coming out heads the first
time (one in two) multiplied by the odds of it coming out tails the second time (one in two)-one
in four. Probability "B" measures the odds of tails being flipped the first time and heads the
second, which is also one in four. So the overall odds of heads being flipped once is A + B, or
one in two (0.25 + 0.25 = 0.5). The sum rule will likewise be of critical importance as you work
through problems. (Also note that, for flipping a coin twice, the odds of flipping heads twice is
0.25, for flipping tails twice it's 0.25, and for flipping a mix is 0.5-which is mathematically
identical to a Punnett square, which you'll also use quite often!)

In solving genetics problems, some of you may prefer to use fractions, while others may
prefer using decimals. I find that fractions are easier on simpler problems and decimals are more
useful on more complicated problems, but the answers we provide at the end of the questions
will often help you decide which strategy is best.

Mendel's laws state that genes segregate independently, so allele segregation is a

mutually exclusive event. As a consequence, you can solve most Mendelian inheritance
problems by first drawing the entire family pedigree, drawing the known alleles in the family

3
pedigree, and then deciding which of the rules, product or sum, should be applied. We will
apply these rules using the following example.

A man and his dizygotic

Dizygotic Twins
(fraternal, non-identical) twin come
for genetic counseling. They have
each had children with unrelated
spouses and their two offspring, one I 1 2 3 4
boy and one girl, have fallen madly

.
in love and wish to get married and
have children. If you know that the
son of one fraternal twin carries a II Carrier
1 2
lethal recessive trait, what is the
probability that the daughter of the
other fraternal twin carries the
same lethal recessive trait? III ?
1
A. 50% Figure 1. The pedigree resulting from the first problem.
B. 25%
C. 15%
D. 12.5%

The first step is to draw the family pedigree, which should look like the pedigree drawn
in figure 1. Note that the fraternal twins are treated as brothers (I-2 and I-3); unlike monozygotic
twins, which have a special designation (shown later) there is no special pedigree marking for
dizygotic twins, because they are genetically the same to "regular" siblings, sharing half of their
genome. I put a question mark at the potential child (III-1) because a further question will ask
about the couple's desire to have a child-though technically the current question deals with the
cousin (II-2), not her child. Since as a follow-up, we will ask about the odds of the child being
afflicted by the disease, so it's best to write down all pertinent information.

Next, you want to "trace" the gene over to the cousin (II-2). You'll see that the two
mothers (I-1 and I-4) should not contribute to the equation. If the mother of the boy who carries
the disease gene (II-1) gave him that gene, then his cousin could not possibly have the disease
gene, as she has a different mother. So, for the cousin to have the gene, both fathers must
have the disease gene. Each father would have inherited the disease gene from one of their
parents, and then each would have to pass it on to their child. You are now ready to calculate the
probability that this series of events would have happened so that the cousin (II-2) also carries
the same disease gene.

Since the son (II-1) carries the lethal allele, what are the odds that his father has it? It's
one in two, as the son could have inherited the allele from either his mother or father. Supposing
that the father has it, what would be the odds that his fraternal twin brother has it? If I-2 has the
allele, he must have received it from one of his parents. Since his brother has the same parents,

4
there is a one in two chance that he will
also have the lethal allele. Since the
Dizygotic Twins
brothers are not identical twins, they do
not share the same genome. So, if the
father of the female cousin (I-3) has the I
gene, the odds that he will pass it to his 1 2 3 4
50% 50%
daughter are likewise one in two.
Therefore, in order for the female
cousin (II-2) to have the gene, all of the II Carrier . 1 2
events just described must have taken
50%
place (her uncle having the gene, her
father having the gene, and her having
the gene). Thus, since all of these III ?
events must occur for her to carry the 1
gene the separate probabilities for each Figure 2: Probabilities for each individual to inherit
event are multiplied together, leading to 0.5 x the lethal allele from their parents.
0.5 x 0.5 = 0.125, or 12.5% (see figure 2). This
is answer "D" from the original question.

If you want to calculate the odds of a child (III-1) of this union having the disease, you
need to figure the probability that each parent would pass the defective allele to their child, and
then MULTIPLYING each individual probability (since both events would have to happen for
the child to express the recessive disease). The probability of the father passing on the allele is
one in two (you already know he has the defective allele, so there is a 50% chance of passing it
to his child). The probability of the mother passing it on to her child is 50% if she had the allele,
but there is only a 12.5% chance that she has the allele. Thus, the probability that she would pass
this defective gene to her child is (50%) times (12.5%), or 6.25%. Multiplying 50% times 6.25%
(the independent probabilities of each parent passing the defective allele to their child) gives a
final answer of 3.125%, or 1 in 16.

The answer to this question will change if Monozygotic Twins

the twins are monozygotic (identical), however.
Consider, then if two monozygotic twins come in
with the same question as the fraternal twins of the
previous question. The risk for the daughter of twin I 2 4
1 3
#2 carrying the same recessive lethal trait as the
son of twin #1 (who is known to carry the trait) is:
II Carrier . 1 2
A. 50%
B. 25%
C. 15% III ?
D. 12.5% 1
Figure 3: Pedigree if the twins are
The pedigree for this question is shown in monozygotic.

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figure 3. It is important to note that individuals I-2 Monozygotic Twins
and I-3 have identical genotypes, since they are
monozygotic twins. Thus, when one calculates
probabilities, the thinking should go like this.
There is a 50% chance that individual I-2 carries the I
recessive allele (as discussed above). However, if 1 2 3 4
50% 100%

.
individual I-2 carries the defective allele, then there
is a 100% chance that I-3 also carries that allele, as II Carrier
their genotypes are identical. There is then a 50% 1 2
50%
chance that I-3 will pass the gene to II-2. This
means that the probability of II-2 carrying the
defective allele is 50% times 100% times 50%, or III ?
1
25% (answer B). These probabilities are shown in
figure 4. Figure 4: Probability calculations for
monozygotic twins.
X-linked Traits

Solving genetics problems involving sex-linked traits can become confusing at times. For
instance, consider the following problem:

A man has an X-linked recessive disease. What is the risk that his daughters will carry
this recessive gene?

A. 50%
B. 100%
C. 67%
D. 33%

The answer is "B." Remember that a male’s sex chromosomes are one X and one Y. For
the father to have a daughter (chromosomal constitution XX) the father MUST transmit his X
chromosome to his daughter. Since the father only had one X chromosome to begin with, and it
carries a disease allele, the daughters will inherit the disease allele and will be carriers for the
disease. Since the daughters presumably inherited a normal X allele from their mother, the odds
that the daughters will develop the disease is very low.

Population Genetics

Solving a problem in population genetics relies on the use of the Hardy-Weinberg

equation, which is derived by applying Mendel's laws to randomly mating populations. Consider
a gene locus with alleles A and a. If you let the frequency of A be designated by the variable "p"
and the frequency of a by variable "q," then if all alleles at this locus are either A or a, then p + q
= 1. The frequency of sperm or egg cells in the population carrying A or a will thus be "p" or "q,"
respectively. If we assume that the union of germ cells carrying either A or a is entirely random,
we can easily calculate the frequency of zygotes having the genotype AA, Aa, or aa - it will

6
resemble a Punnett square, as shown in figure 5.

Keep in mind that this Punnett square

Eggs
shows a calculation for both alleles and
Sperm
frequencies, and the Hardy-Weinberg A a allele
equation applies to frequencies. Thus Hardy allele frequency p q frequency
and Weinberg squared the equation p + q = 1
to show that p2 + 2pq + q2 = 1, where: AA Aa
A p p2 pq
a. the frequency of AA equals p2, the
dominant homozygote frequency
b. the frequency of Aa equals 2pq, the aA aa
heterozygote frequency, and a q qp q2
c. the frequency of aa equals q2, the
recessive homozygote frequency.
Figure 5: Hardy-Weinberg equilibria.
The Hardy-Weinberg equation is applicable if
certain assumptions are met, namely that there is random mating in a fairly large, stable
population (i.e. of several hundred individuals that don't migrate), that there is a negligible
mutation rate, that there is no natural selection, and that all the genotypes are viable and fertile.
Clearly, this is not always true, but essentially all population genetics questions you will be
asked will consider these assumptions to be valid. (We will have more to say about Hardy-
Weinberg in a later chapter.)

With Hardy-Weinberg in hand, you should be able to solve the following question:
The frequency of Sickle-cell anemia in the African-American population is about 1 in 400. What
is the risk of a random African-American being a non-carrier for Sickle-cell anemia?

A. 100%
B. 98%
C. 90%
D. 50%

Since you know that the Sickle-cell disease is a recessive disorder, one can assign the
frequency of the sickle-cell gene in the population as q. The incidence of the disease, then, is q2,
which we know to be 1 in 400. We find the value of q by taking the square root, so that q = 1/20.
What does this tell us? We know that 2pq equals the heterozygote, i.e. the carrier, population.
Since p + q = 1 and q = 1/20, p = 19/20. To calculate 2pq you don't need to pull out a calculator-
19/20 is roughly equivalent to 1, so 2pq = 2 (1) (1/20) = 1/10. Thus, the odds of being a carrier of
the Sickle-cell trait as a randomly-chosen African-American is 10%, and the odds that you are a
non-carrier are 90%, or answer "C."

You can couple the product or sum rule to the Hardy-Weinberg equation, as the
following problem illustrates. Suppose two African-American individuals come to you for

7
genetic counseling and are concerned about their risk of having children with Sickle-cell anemia.
Which one of the following most closely approximates their risk for having an affected child
with Sickle-cell disease?

A. 1:100
B. 0
C. 1:4
D. 1:400
E. 1:2500

You know, from the previous question, that the odds of being a carrier are one in ten. So,
in order for the child to have the disease, both parents must be carriers and both parents must
pass on the disease gene. Since there is a ½ chance of passing on the bad gene if you carry it,
the odds of passing on the bad gene are 50% times 10% (the chance the mother or father is a
carrier). This comes out to 1/20 for each parent. For the child to have the disease, he/she must
have inherited a disease allele from each parent, which means that the odds of that occurring are
1/20 times 1/20, or one in 400, answer D. At some basic level, this should make sense: the odds
that any African American child will have the disease is 1 in 400, whether they came into your
office for counseling or not, since that is the disease prevalence.

Population genetics problems that involve sex-linked traits use the same principles. Take
the following two questions:

Fabry disease, an X-linked recessive disease, has a mutant gene frequency of 1:40,000 in
the general population. What is the frequency of affected males in that population? Using the
same answers below, what is the frequency of carrier females?

A. 1:1.6 x 109
B. 1:40,000
C. 1:20,000
D. 1:200

It might be tempting to simply square q (1/40,000) to arrive at answer "A," but that would
be wrong. Because this is a sex-linked trait, any male who receives a "q allele" will have the
disease since that allele is located on the only X chromosome they receive. It might then be
tempting to pick answer "C," concluding that an affected male's genotype is pq, and 2pq = 2 (~1)
(1/40,000) = 1/20,000. But "2pq" refers to when the individual has two alleles at the locus, in this
case, only for females. So, the number of carrier females is 2pq, or one in 20,000. Another way
of looking at this problem is to say that if 40,000 males were in a room, this would represent
40,000 X-chromosomes. There is a 1/40,000 chance that one of those X chromosomes would
carry the disease gene, so the frequency of men with the disease would be 1/40,000. Similarly, if
there were 20,000 females in a room, that would represent 40,000 X-chromosomes, and one
would be a carrier.

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What happens if alleles are not in “equilibrium”? Linkage equilibrium describes the situation
in which the allele frequencies in a large population have the same value that they would have if
the genes at each locus were combined at random. Sometimes, in a sub-population one of the
alleles may be under selection and we get a phenomenon called linkage disequilibrium (LD). The
detection of “LD” for specific alleles in some diseases sometimes is a clue that the allele may
play some role in the disease. You will learn more about this when we discuss “complex” traits
later in this series.

Working through the problems that follow will help to illustrate the points in this lecture,
and allow you to feel secure in working out genetic probability questions.

9
Sample Questions (All problems, with explanations, are on the web at the Medical
Biochemistry Blackboard site)

1. Two individuals who have the same autosomal recessively inherited disease marry and
come to you for genetic counseling about their risks of affected children. Which ONE of
the following statements is true?

A. Their risk for an affected fetus is 100%

B. Their children will have identical phenotypes to them.
C. An oligonucleotide probe used to detect the genetic alterations in the father will
necessarily detect the same alterations in the mother.
D. All affected children will have the same alleles at the disease locus.

2. The frequency of Sickle Cell anemia in the black population is about 1:400. What is the
"risk" of a random black individual being a non-carrier for Sickle Cell anemia?

A. 100%
B. 98%
C. 90%
D. 50%

3. A man with Huntington's chorea, an autosomal dominant trait, comes to you for genetic
counseling. What is the risk of any of his offspring having the Huntington's disease
genes?
A. 75%
B. 25%
C. 50%
D. 100%
E. 10%

4. In question 3 we now assume that the person who comes in for counseling is a woman
affected with Huntington's chorea? What is the risk of any of her offspring having the
Huntington's disease gene?

A. 75%
B. 25%
C. 50%
D. 100%
E. 10%

10
5. Two African American individuals come to you for genetic counseling and are concerned
about their risks of having children with Sickle Cell disease. Which ONE of the
following most closely approximates their risk for having an affected child with Sickle
Cell disease?

A. 1:100
B. 0
C. 1:4
D. 1:400
E. 1:2500

6. A man and his dizygotic (fraternal) twin come for genetic counseling. They have each
had children with unrelated spouses and their two offspring, one boy and one girl, have
fallen madly in love and wish to get married and have children. If you know that the son
of one fraternal twin carries a lethal recessive trait, what is the probability that the
daughter of the other fraternal twin carries the same lethal recessive trait?

A. 50%
B. 25%
C. 15%
D. 12½%

7. Two monozygotic twins come in with the same question as the fraternal twins of question
#7. The risk for the daughter of twin two carrying the same recessive lethal trait as the
son of twin one is known to carry is:

A. 50%
B. 25%
C. 15%
D. 12½%

8. In the pedigree shown to the right, I-1 is

known to carry a particular autosomal gene.
What is the risk that III-1 and III-2 both
carry the same gene?

A. 1:8
B. 1:16
C. 1:32
D. 1:64

11
9. A man has a X-linked recessive disease. What is the risk that his daughters will carry this
recessive gene?

A. 50%
B. 100%
C. 67%
D. 33%

10. Two sets of identical twins meet. The two brothers and the two sisters decide they hit it
off very well and one of each pair, marry and have children, who are girls. Which ONE
of the following statements is true about the girl cousins who are born?

A. The composition of their genomes will be the same.

B. Their genetic relationship is the same as for siblings.
C. Are genetically related as first cousins.
D. Are more closely related genetically than usual siblings.

POPULATION GENETICS PROBLEMS

11. The gene frequency for a particular genetic autosomal recessive trait in the population is
1:50. Under the assumptions for Hardy-Weinberg equilibrium, the heterozygote
frequency is:

A. 1:50
B. 1:2500
C. 1:625
D. 1:25

12. Fabry disease, an X-linked recessive disease, has a gene frequency for mutant allele of
1:40,000 in the general population. What is the frequency of affected males in that
population?

A. 1:1.6 x 109
B. 1:40,000
C. 1:20,000
D. 1:200

13. For Fabry disease in the previous question, what is the frequency of carrier females in the
general population?

A. 1:1.6 x 109
B. 1:40,000
C. 1:20,000
D. 1:200

12
14. You are a member of Congress interested in genetic screening. A particular disease you
are interested in has a frequency in the population of 1:2500. You are proposing a
program to screen pregnant females for carrier status for this disease. There are about
3,000,000 births per year in the population that you are interested in and the cost of the
program will be about $25,000,000. What is the dollar cost to detect one carrier for this
disease?

A. $8.33
B. ~ $420.
C. ~ $210.
D. ~ $105

15. In the above question, a total cost to determine whether or not this woman and her
husband are at risk for having a child with the disease in question, is?

A. ~ $17.00
B. ~ $840
C. ~ $220
D. ~ $100

13
Answers to the problems

1. A
2. C
3. C
4. C
5. D
6. D
7. B
8. C
9. B
10. B
11. D
12. B
13. C
14. C
15. C

14
 Index

Allele .............................................................................................................................................. 2-6, 8, 11

Chromosome ............................................................................................................................................6, 8
dominant ..................................................................................................................................................7, 9
genotype ....................................................................................................................................................6,8
Hardy-Weinberg ..................................................................................................................................2,6,11
heterozygote ...........................................................................................................................................7, 11
homozygote ..................................................................................................................................................7
locus .........................................................................................................................................................6, 9
mutation .......................................................................................................................................................7
pedigree .............................................................................................................................................. 2-5, 10
product rule ..............................................................................................................................................2, 3
recessive ........................................................................................................................................ 4-8, 10-11
Segregation ..............................................................................................................................................2, 3
sickle cell disease .......................................................................................................................................10
sum rule................................................................................................................................................2, 3, 7
X-linked .................................................................................................................................................6, 11

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