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1. The answer is (E).
The other enzymes are involved in the replication process in general, but it
is telomerase that can recognize the TTAGGG telomere sequence to that it can be replicated.
2. The answer is (B).
Many antineoplastic drugs act by inhibiting DNA replication.
3. The answer is (A).
Chromosome replication occurs during the S phase of the cell cycle. It
starts when topoisomerase breaks a single strand of DNA, which causes DNA unwinding.
Active genes are replicated early in S and inactive genes late in the S phase. Replication is
semiconservative because there is one intact parental strand in a double helix of DNA and a
newly synthesized strand.
4. The answer is (C).
The lagging strand of DNA is synthesized discontinuously by DNA poly-
merase alpha, which synthesizes Okazaki fragments, which then have to be joined by a
DNA ligase. The leading strand of DNA is synthesized continuously by DNA polymerase
delta.
5. The answer is (B).
In Fanconi anemia, DNA damage goes unrepaired and eventually reaches
a point where the chromosome is unstable. The result is that there is chromosome breakage
with rearrangements of chromosomal material. When a break occurs in a tumor suppressor
gene, or proto-oncogenes are activated by chromosome rearrangements, the development
of a malignancy is likely.
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26
I. AUTOSOMAL DOMINANT INHERITANCE
A. Introduction.
In autosomal dominant inheritance:
1.
The disorder is observed in an
equal number of females and males
who are
heterozygous
for
the mutant gene.
2.
The characteristic
family pedigree is vertical
in that the disorder is passed from one gener-
ation to the next generation.
3. Transmission by the mother or father
(i.e., mother-to-son; mother-to-daughter; father-to-
son; father-to-daughter).
4.
Although homozygotes for some autosomal dominant disorders do occur, they are rare
because homozygosity for an autosomal dominant disorder is generally a genetic lethal.
B. Genetic Risk Assessment.
The genetic risk associated with an autosomal dominant disorder
is as follows:
1. Example 1. Affected heterozygous mother and normal homozygous father:
In autosomal dom-
inant disorders, the affected parent is usually a heterozygote because homozygosity for an
autosomal dominant allele is frequently a genetic lethal (where those with the disorder
die before they reproduce). In this example, the heterozygous mother has the disorder
caused by the autosomal dominant allele “D” and the father is a normal homozygous
individual. All possible combinations of alleles from the parents are shown in a Punnett
square below.
Conclusion:
There is a
50% chance
(2 out of 4 children) of having a child with the autoso-
mal dominant disorder (Dd) assuming complete penetrance. There is a 50% chance (2 out
of 4 children) of having a normal child.
2. Example 2. Affected heterozygous mother and affected heterozygous father:
In some autoso-
mal dominant disorders (e.g., achondroplasia), it is not unusual for individuals to choose
partners who have the same condition. The parents may actually be more concerned
about the chances of having a child with normal stature than one with achondroplasia. As
mentioned above, homozygosity for an autosomal dominant allele is frequently a genetic
lethal so that both parents with achondroplasia would be heterozygous. In this example,
the heterozygous mother and the heterozygous father have the disorder caused by the
Mother
D
d
Father
d
Dd
dd
d
Dd
dd
LWBK274-C04_26-44.qxd 06/02/2009 03:34 PM Page 26 Aptara
autosomal dominant allele “D.” All possible combinations of alleles from the parents are
shown in a Punnett square below.
Conclusion:
There is a
50% chance
(2 out of 4 children) of having a child with achon-
droplasia (Dd); a
25% chance
(1 out of 4 children) of having a normal child (dd); and a
25%
chance
(1 out of 4 children) of having a child with a lethal condition (DD).
3. Example 3. Affected homozygous mother and normal homozygous father:
In some autosomal
dominant disorders (e.g., Noonan syndrome), homozygosity for an autosomal dominant
allele is not a genetic lethal so that the affected individual would be homozygous. This sit-
uation is exceedingly rare and would most likely occur in cases of consanguinity, where
the parents are related. In this example, the homozygous mother has the disorder caused
by the autosomal dominant allele “D” and the father is a normal homozygous individual.
All possible combinations of alleles from the parents are shown in a Punnett square below.
Conclusion:
There is a
100% chance
(4 out of 4 children) of having a child with Noonan syn-
drome (Dd).
4.
If the parents of the proband are normal, the risk to the siblings of the proband is
very low
but greater than that of the general population because the possibility of germ line
mosaicism exists.
C. New Mutations.
In autosomal dominant disorders, new mutations are relatively common. In
these cases, there will be an affected child with no family history of the disorder. There is a
low recurrence risk (1%–2%) due to the possibility of germ line mosaicism. Germ line
mosaicism is the presence of more than one cell line in the gametes in an otherwise normal
parent and is the result of a mutation during the embryonic development of that parent.
There is an increased risk for a new dominant mutation in fathers over 50 years of age.
D. Reduced Penetrance.
In a reduced penetrance, many individuals have the disorder mutation
but do not develop disorder symptoms. However, they can still transmit the disorder to their
offspring. Example: Breast cancer whereby many women have mutations in the BRCA1 gene
and BRCA2 gene but do not develop breast cancer. However, some women have mutations in
the BRCA1 gene and BRCA2 gene and do develop breast cancer.
E. Variable Expressivity.
In variable expressivity, the severity of the disorder can vary greatly
between individuals. Some people may have such mild disorder that they do not know they
have it until a severely affected child is born. Example: Marfan syndrome whereby a parent is
tall and has long fingers, but one of his children is tall, has long fingers, and has serious car-
diovascular defects.
F. Pleiotropy.
Pleiotropy refers to a situation when a disorder has multiple effects on the body.
Example: Marfan syndrome whereby the eye, skeleton, and cardiovascular system may be
affected.
Mother
D
D
Father
d
Dd
Dd
d
Dd
Dd
Mother
D
d
Father
D
DD
Dd
d
Dd
dd
Chapter 4
Mendelian Inheritance
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G. Locus heterogeneity.
In locus heterogeneity, genes at more than one locus may cause the dis-
order. Example: Osteogenesis imperfecta whereby collagen a-1 (I) chain protein and colla-
gen a-2(I) chain protein are encoded by the COL1A1 gene on chromosome 17q21.3-q22 and
COL1A2 gene on chromosome 7q22.1, respectively (i.e., two separate genes located on dif-
ferent chromosomes). A mutation in either gene will cause osteogenesis imperfecta.
H. Example of an Autosomal Dominant Disorder. Noonan Syndrome (NS).
1.
NS is an autosomal dominant genetic disorder caused by mutations in the following genes:
a.
The
PTPN11 gene
on
chromosome 12p12.1
which encodes for
tyrosine-protein phos-
phatase non-receptor type 11
in
50% of NS cases. This is an extracellular protein that
plays a key role in the cellular response to growth factors, hormones, and cell adhesion
molecules.
b.
The
RAF1 gene
on
chromosome 3p25
which encodes for
RAF proto-oncogene serine/
threonine-protein kinase
in 3–17% of NS cases. This protein plays a key role in the signal
transduction pathway for epidermal growth factor (EGF) action.
c.
The
SOS1 gene
on
chromosome 2p22 – p21,
which encodes for
son-of-sevenless homolog
1
in
10% of NS cases. This protein plays a key role in the signal transduction pathway
for receptor tyrosine kinase action.
2.
Many NS individuals have
de novo
mutations. However, an affected parent is recognized in
30% to 75% of families. In simplex cases (i.e., those with no known family history), the
mutation is inherited from the father.
3. Prevalence.
The prevalence of NS is 1/1,000 to 2,500 births.
4. Clinical features include:
short stature, congenital heart defects, broad or webbed neck,
unusual chest shape (e.g., superior pectus carinatum, inferior pectus excavatum), appar-
ently low-set nipples, cryptorchidism in males, characteristic facial appearance (e.g., low-
set, posteriorly rotated ears; vivid blue irides; widely-spaced eyes; epicanthal folds; and
thick, droopy eyelids).
II. AUTOSOMAL RECESSIVE INHERITANCE
(Figure 4-1C; Tables 4-1, 4-2,
A. Introduction.
In autosomal recessive inheritance:
1.
The disorder is observed in an
equal number of females and males
who are
homozygous
for
the mutant gene.
2.
The characteristic
family pedigree is horizontal
in that the disorder tends to be limited to a
single sibship (i.e., the disorder is not passed from one generation to the next generation).
3. Mother and father each transmit a recessive allele
to their sons or daughters.
4.
Both parents are
obligate heterozygous carriers
whereby each parent carries one mutant
allele and is asymptomatic (unless there is uniparental disomy or consanguinity, which
increases the risk for autosomal recessive disorders in children).
B. Genetic Risk Assessment.
The genetic risk associated with an autosomal recessive disorder is
as follows:
1. Example 1. Normal heterozygous mother and normal heterozygous father:
In autosomal
recessive disorders, both parents are carriers of a single copy of the responsible gene. In
this example, the mother and father are normal heterozygous carriers of the autosomal
recessive allele “r.” All possible combinations of alleles from the parents are shown in a
Punnett square below.
Mother
R
r
Father
R
RR
Rr
r
Rr
rr
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BRS Genetics
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Conclusion:
There is a
25% chance
(1 out of 4 children) of having a child with the autoso-
mal recessive disorder (rr), a
50% chance
(2 out of 4 children) of having a normal child that
will be a heterozygous carrier (Rr), and a
25% chance
(1 out of 4 children) of having a nor-
mal child that will not be a carrier (RR).
In autosomal recessive disorders, one can calculate the genetic risk for the normal chil-
dren being homozygous or heterozygous. In this calculation, the child with the autosomal
recessive disorder (rr
X) is eliminated from the calculation. In this example, the mother
and father are normal heterozygous carriers of the autosomal recessive allele “r.” All pos-
sible combinations of alleles from the parents are shown in a Punnett square below.
Conclusion:
There is a
66% chance
(2 out of 3 children) of having a normal child that is a
heterozygous carrier (Rr). There is a
33% chance
(1 out of 3 children) of having a normal
child that is homozygous (RR).
2. Example 2. Affected homozygous mother and normal homozygous father:
In this example, the
mother has the disorder caused by the autosomal recessive allele “r” and the father is a
normal homozygous individual. All the possible combinations of alleles from the parents
are shown in a Punnett square below.
Conclusion:
There is a
100% chance
(4 out of 4 children) of having a child who is a normal
heterozygous carrier (Rr).
3. Example 3. Affected homozygous mother and normal heterozygous father:
In this example,
the mother has the disorder caused by the autosomal recessive allele “r” and the father is
a normal heterozygous carrier. All the possible combinations of alleles from the parents
are shown in a Punnett square below.
Conclusion:
There is a
50% chance
(2 out of 4 children) of having a child with the autoso-
mal recessive disorder (rr). There is a
50% chance
(2 out of 4 children) of having a child who
is a normal heterozygous carrier (Rr).
C. Example of an Autosomal Recessive Disorder. Cystic Fibrosis (CF).
1.
CF is an autosomal recessive genetic disorder caused by
1,000 mutations (almost all are
point mutations or small deletions 1-84 bp) in the
CFTR gene
on
chromosome 7q31.2
for the
cystic fibrosis transmembrane conductance regulator
which functions as a chloride ion (Cl
)
channel. The Cl
ion channel normally transports Cl
out of the cell and H
2
O follows by
osmosis. The H
2
O maintains the mucus in a wet and less viscous form.
2.
CF is most commonly (
70% of cases in the North American population) caused by a
three base deletion
which codes for the amino acid
phenylalanine at position 508
(delta
F508) such that phenylalanine is missing from CFTR. However, there are a large number
Mother
r
r
Father
R
Rr
Rr
r
rr
rr
Mother
r
r
Father
R
Rr
Rr
R
Rr
Rr
Mother
R
r
Father
R
RR
Rr
r
Rr
X
Chapter 4
Mendelian Inheritance
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