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1. The answer is (A).
When the proband is of the less affected sex, more of the genetic and
environmental factors that contribute to the condition are present and subsequent siblings
are at a higher risk for the condition because of that. There is also a greater risk to a sibling
if the proband is more severely affected, if there are multiple family members affected, or if
the affected family member is a first-degree relative.
2. The answer is (D).
The threshold of liability is reached when the environmental and genetic
factors that contribute to a trait reach a level where the trait occurs.
3. The answer is (B).
Because isolated clubfoot is more common in males than in females, the
fact that the daughter III-1 has the condition raises the risk to subsequent siblings. Male
siblings will be at a greater risk than female siblings, but the risk is elevated for both. Thus,
the male fetus III-2 is at the highest risk for isolated clubfoot. None of the other pregnan-
cies in the family are first-degree relatives so the risk is lower for them.
4. The answer is (C).
For multifactorial disorders, the risk of recurrence for first-degree rela-
tives is approximately the square root of its incidence.
5. The answer is (C).
When the affected child in the family is of the less-affected sex, then the
recurrence risk for an opposite sex sibling is higher but the risk to a same sex sibling is also
increased. This is because if the less-affected sex is affected by a disorder then there are
more of the environmental and genetic factors that cause the disorder present, thus lower-
ing the threshold of liability and increasing the recurrence risk.
6. The answer is (A).
Heritability increases as the concordance between monozygotic twins
for a trait increases versus the concordance in dizygotic twins. Because the difference in
concordance for cleft palate between monozygotic and dizygotic twins is not very large,
heritability is low and there is not a very large genetic component.
7. The answer is (D).
Consanguinity increases the risks for birth defects in general and confers
a high risk of sharing predisposing genes. Having a third-degree relative with a multifactor-
ial disorder does not increase recurrence risk above the population risk and there is only a
slight risk with a second-degree relative with mild disease.
8. The answer is (B).
It is thought that alleles linked to the HLA-DR3 and HLA-DR4 genes alter
the immune response such that an immune response to an environmental antigen like a
virus gets out of control and destroys the pancreatic beta cells that make insulin. In Type 2
diabetes, there is almost always some insulin production, but individuals with this condi-
tion develop insulin resistance. The genetic component of this disease is not well under-
stood.
9. The answer is (C).
Having a first-degree relative increases recurrence risk for heart disease
and having a female first-degree relative (least-affected sex) confers an even higher risk.
10. The answer is (D).
Human papilloma viruses have been implicated as a factor in the devel-
opment of cervical carcinoma. A vaccine has been developed to stop infection with the
virus and help prevent the development of cervical cancer.
11. The answer is (D).
If a disorder is entirely due to environmental factors, then H
0. If the
disorder is entirely genetic, then H
1. A multifactorial disorder would have a value for H
somewhere between these two figures because there are both environmental and genetic
factors involved in developing the disorder.
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71
Population genetics is the study of the distributions of genes in populations. In addition,
population genetics concerns itself with the factors that maintain or change the frequency of
genes (i.e.,
gene [allele] frequency
) and frequency of genotypes (i.e.,
genotype frequency
) from
generation to generation.
A.
The
disease frequency
is the frequency that a genetic disorder is observed in a population. It
is calculated by data-mining hospital records and is expressed as, for example, 1 in 150,000
people.
B.
The
mutation frequency
is the frequency that a mutation occurs in the DNA. The mutation fre-
quency is expressed as the
number of mutations per locus per gamete per generation.
C.
A
gene
is the basic unit of hereditary composed of a finite number of nucleotides arranged in
a specific sequence that interacts with the environment to produce a trait.
D.
An
allele
is an alternative (or mutated) version of a gene or DNA segment.
E.
A
locus
is the physical location of a gene or DNA segment on a chromosome. Since chromo-
somes are paired in humans, humans have two alleles at each locus.
F.
A
polymorphism
is the occurrence of two or more alleles at a specific locus in frequencies
greater than can be explained by mutations alone. Polymorphisms are common in noncod-
ing regions of DNA (i.e., introns). A polymorphism does not cause a genetic disorder. A poly-
morphism can be used as a
genetic marker
for a gene (e.g., the DMD gene on chromosome
Xp21.2 for dystrophin related to Duchenne muscular dystrophy) if the polymorphism and
the DMD gene are closely linked.
G. Single nucleotide polymorphisms
are silent mutations that accumulate in the genome.
H.
A
restriction fragment length polymorphism (RFLP)
is a polymorphism that either creates or
destroys a restriction enzyme site. RFLPs are abundant throughout the human genome.
RFLPs are used in
gene linkage
or
gene mapping
studies.
See Figure 8-1A.
I.
A
variable number tandem repeat (VNTR) polymorphism
is a polymorphism whereby DNA
sequences are repeated in tandem in the human genome between restriction enzyme sites a
variable number of times. Because VNTRs are extremely polymorphic, two unrelated people
cannot exhibit the same genotype. VNTRs are used in
DNA fingerprinting
and
forensic medi-
cine
to establish paternity; zygosity; or identity from a blood, semen, or other DNA sample.
In general, VNTRs are better markers than RFLPs.
See Figure 8-1B.
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72
BRS Genetics
Bgl II
p
q
Bgl II
Bgl II
30 kb
Bgl II
p
q
Bgl II
Bgl II
22 kb
8 kb
Bgl II
Subject #1
Subject #2
Bgl II
p
q
Bgl II
Bgl II
30 kb
Bgl II
p
q
Bgl II
Bgl II
32.4 kb
Subject #1
Subject #2
Subject
#2
Subject
#1
22 kb
8 kb
30 kb
Agarose gel
electrophoresis
Subject
#2
Subject
#1
32.4 kb
30 kb
Agarose gel
electrophoresis
A
B
FIGURE 8-1. RFLPs and VNTRs. (A) RFLPs.
In subject 1, two Bgl II restriction enzymes sites are present at a certain locus
on a chromosome, which produces a 30 kb fragment that is observable with agarose gel electrophoresis. In subject 2,
three Bgl II restriction enzyme sites are present at a certain locus on a chromosome, which produces a 22 kb and an 8 kb
fragment that is observable with agarose gel electrophoresis. Consequently, subject 2 has a restriction fragment length
polymorphism. (B) VNTRs. In subject 1, two Bgl II restriction enzymes sites are present at a certain locus on a chromo-
some, which produces a 30 kb fragment that is observable with agarose gel electrophoresis. In subject 2, two Bgl II
restriction enzymes sites are present at a certain locus on a chromosome, which produces a 32.4 kb fragment that is
observable with agarose gel electrophoresis. The VNTR has 40 tandem repeats of 60 base pairs (40
60 2,400 base
pairs) inserted to produce the 32.4 kb fragment.
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J.
A
genotype
is the gene constitution at a specific locus or the specific mutations present in a
given disorder.
K.
A
phenotype
is the observed physical or clinical findings in a normal person or affected
patient, respectively.
A. Hardy-Weinberg Principles.
1.
The Hardy-Weinberg Law explains that the allele frequencies do not change from genera-
tion to generation in a large population with random mating.
2.
The Hardy-Weinberg Law explains that the genotype frequency is determined by the rela-
tive allele frequencies at that locus.
3.
The Hardy-Weinberg Law relates the genotype frequency at a locus to the phenotype fre-
quency in a population.
B. Hardy-Weinberg Equation.
In a population at equilibrium, for a locus with two alleles (A and
a) with allele frequencies of p and q, respectively: the genotype frequencies are determined
by the binomial expansion
(p
q 1)
2
or
p
2
2pq q
2
1.
Therefore, the genotype fre-
quencies are
AA
p
2
, Aa
2pq,
and
q
2
aa.
This is illustrated by the following Punnett
square:
C. Hardy-Weinberg Assumptions.
The Hardy-Weinberg Law applies if the following assumptions
are met:
1. There is a large population so that there is no influence of genetic drift or the founder effect.
a.
Genetic drift is a fluctuation in allele frequency
due to chance
operating on a small gene
pool contained within a small population. In a small population, random factors such
as fertility or survival of mutation carriers can cause the allele frequency to rise for rea-
sons other than the mutation itself.
b.
The founder effect is genetic drift that occurs when one of the founders of a new popu-
lation carries a rare allele that will have a far higher frequency that it did in the larger
population from which the new population is derived. Examples include:
Huntington
disorder
in Lake Maracaibo, Venezuela and
variegate porphyria
in Afrikaner populations
of South Africa.
2. There is random mating (panmixia) with no stratification, assortative mating or consanguinity.
a.
Stratification refers to a population where there are subgroups that have remained, for
the most part, genetically distinct. An example would be cystic fibrosis, where the car-
rier frequency of the disorder is 1/25 in Caucasian, 1/30 in Ashkenazi Jewish, 1/46 in
Hispanic, 1/65 in African American, and 1/90 in Asian American populations.
b.
Assortative mating is where the choice of a mate is because of some particular trait. An
example of this would be a deaf person preferring another deaf person as a mate.
c.
Consanguinity is where the two mates are related. Progeny from a marriage between
first cousins is an example where this would apply.
3. There is a constant mutation rate where genetically lethal alleles (causing death or steriliza-
tion) are replaced by new mutations.
If lethal alleles were not replaced by new mutations,
the allele frequency would change with each generation and quickly reach zero.
Male Population
A (p)
a (q)
Female Population
A (p)
AA (p
2
)
Aa (pq)
a (q)
Aa (pq)
aa (q
2
)
Chapter 8
Population Genetics
73
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4. There is no selection for any of the genotypes at a locus.
Selection acts upon the fitness of a
genotype, with
fitness (f )
being a measure of the offspring possessing the genotype that
survive to reproduce. A coefficient of selection can be determined, which is 1 – f.
a.
If the allele determining the genotype is as likely to be present in the next generation as
any other allele, then
f
1.
b.
If the allele is a genetic lethal, causing death or sterility, then
f
0.
c.
If an allele is deleterious so that fewer than normal offspring with the allele are repre-
sented in the next generation, then
f
1.
5. There is no migration; no gene flow into or out of the population.
Genes from a migrant popu-
lation are gradually merged into the gene pool of the population into which they migrated,
which can change gene frequencies. Gene flow between populations can slowly change
frequencies in both populations making them more similar to each other. For example, the
frequency of sickle cell trait is lower in African Americans than in West African populations
because of the admixture with other ethnic groups in the United States.
III. HARDY-WEINBERG AND AUTOSOMAL
In autosomal dominant disorders, homozygosity is exceedingly rare in the population since
this is a genetic lethal genotype most of the time. A good example of this is
achondroplastic
dwarfism.
Homozygosity for achondroplastic dwarfism is a genetic lethal so that no individ-
uals with this genotype survive to birth. Therefore, individuals in the population with achon-
droplastic dwarfism are heterozygotes. An exception to this is
Huntington disorder
where
homozygosity for Huntington disorder has the same clinical severity as the heterozygosity.
Example 8-1. Achondroplasia Dwarfism
Question:
A recent study of achondroplasia dwarfism documented 7 new cases out of 250,000
in the US population. In achondroplasia dwarfism, homozygosity is a genetic lethal. What is
the allele frequency of the achondroplasia dwarfism disease gene in the U.S. population?
Solution:
1.
7 new cases out of 250,000 means that achondroplasia dwarfism occurs in the U.S. pop-
ulation at a
disease frequency of 1 in 35,714 or 0.000028
(7/250,000).
2.
All the genotypes containing the achondroplasia disease gene include only the het-
erozygotes (Dd;2pq) since homozygosity is a genetic lethal. Thus, the frequency of het-
erozygotes (2pq) is equal to the disease frequency
(2pq
0.000028).
3.
The allele frequency (p) of the disease gene (D) is usually very small in autosomal domi-
nant disorders and the allele frequency (q) of the other allele (d) is
1. Consequently,
2p(1) or 2p equals the disease frequency. This means that
2p(1)
0.000028
or
2p
0.000028
or
p
0.000014.
In conclusion, the allele frequency (p) of the achondroplasia
dwarfism disease gene is
0.000014
or
1 in 71,428.
Example 8-2. Huntington Disorder
Question:
Data-mining of the clinical records of a large number of U.S. hospitals indicates
that Huntington disorder occurs in the U.S. population at a disease frequency of 1 in 10,000
or 0.0001. In Huntington disorder, homozygosity is not a genetic lethal. What is the allele
frequency of the Huntington disease gene in the U.S. population?
Solution:
1.
All the genotypes containing the Huntington disease gene include the homozygotes
(DD; p
2
) and heterozygotes (Dd; 2pq). Thus, the frequency of the homozygotes (DD; p
2
)
and heterozygotes (Dd; 2pq) is equal to the disease frequency
(p
2
2pq 0.0001).
2.
The frequency of homozygotes (p
2
) is very small (
0) and the allele frequency (q) is 1.
Consequently, 2p(1) or 2p equals the disease frequency. This means that
2p(1)
0.0001
or
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