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50
BRS Genetics
A
B
C
D
E
F
G
H
FIGURE 5-2. Dynamic mutations. (A) Fragile X syndrome.
Photograph shows a young male with a prominent forehead and
jaw, a long face, and large, dysmorphic ears. (B) Friedreich ataxia. Photograph shows a section of the spinal cord stained
specifically for axons (healthy axons stain black). Note the degeneration of the posterior columns (arrow, whitish areas),
lateral corticospinal tract, and possible the spinocerebellar tracts. (C,D,E ) Myotonic dystrophy. (C) Photograph of a young
male shows limited facial expression and inability to fully open the eyes due to weakness of the facial muscles. (D)
Photograph of a young male shows an inability to fully close the eyes tightly or generate brow furrows due to weakness
of the facial muscles. (E) Photograph of a young male shows fasciculations of the tongue due to delayed muscle relaxation
after contraction. (F,G,H) Huntington disorder. (F) Pathological specimen shows atrophy of the caudate nucleus is appar-
ent (arrows). (G) Coronal proton-density scan shows atrophy of the caudate nucleus (arrows) and dilatation of the frontal
horns of the lateral ventricles (*). (H) MRI T2-weighted image shows high signal intensity in the globus pallidus (arrows).
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1.
The repeat size of each individual’s FMR-1
gene or genes is noted on the pedigree
below. Which person has a full mutation in
the FMR-1 gene and would have Fragile X
syndrome?
(A)
person A
(B)
person B
(C)
person C
(D)
person D
4.
One of the mechanisms by which genes
are imprinted is which of the following?
(A)
change in DNA sequence
(B)
methylation of genes
(C)
heteroplasmy
(D)
trisomy rescue
5.
If a sperm from the father with two copies
of chromosome 15 fertilizes an egg from the
mother that has no copies of chromosome
15, the conceptus would have the normal
disomic complement of chromosome 15.
Assuming that the conception goes to term,
which one of the following phenotypes
would the child have?
(A)
normal
(B)
Angelman syndrome
(C)
Prader-Willi syndrome
(D)
Beckwith-Wiedemann syndrome
6.
The second leading cause of inherited
mental retardation is caused by highly
expanded repeats outside of a gene on the X
chromosome, which may result in hyperme-
thylation of the gene so that it is not
expressed. The syndrome that results from
these highly expanded repeats is which one
of the following?
(A)
Friedreich ataxia
(B)
Myotonic dystrophy
(C)
Fragile X
(D)
Spinocerebellar ataxia type 3
9 repeats
62/10
repeats
170/10
repeats
12 repeats
10
repeats
10/12
repeats
500
repeats
A
B
C
D
2.
In myotonic dystrophy, the severity of the
disease increases with each succeeding gen-
eration. Which of the following best
describes this phenomenon?
(A)
anticipation
(B)
incomplete penetrance
(C)
genomic imprinting
(D)
variable expressivity
3.
A conception is trisomic for chromosome
7. During the first cell division, the paternal
chromosome 7 is lost, leaving two maternal
chromosome 7’s in the daughter cells. The
daughter cells will thus have which one of
the following?
(A)
uniparental disomy
(B)
monosomy 7
(C)
double trisomy
(D)
a deletion
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1. The answer is (D).
The full mutation threshold for Fragile X is reached when there are
200
repeats.
2. The answer is (A).
Anticipation means that the severity of the disease increases with each
generation, and/or the age of onset decreases with each generation.
3. The answer is (A).
Because both chromosome 7’s in the daughter cells came from one par-
ent, the mother, the daughter cells have uniparental disomy.
4. The answer is (B).
The gene from one parent that is methylated is not expressed, but the
gene on the chromosome from the opposite sex is expressed.
5. The answer is (B).
Because there are no maternal copies of the Prader-Willi/Angelman genes
present, this is equivalent to a deletion of that area of the maternal chromosome 15 and
Angelman syndrome will result.
6. The answer is (C).
The CGG repeat in Fragile X is outside the FMR1 gene on the X chromo-
some. The threshold for the manifestation of Fragile X syndrome is
200 repeats.
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53
Mitochondria are involved in: oxidative phosphorylation (which causes the
synthesis of
adenosine triphosphate [ATP]
driven by electron transfer to oxygen), the production of acetyl
coenzyme A (CoA), the tricarboxylic acid cycle, fatty acid b-oxidation, amino acid oxidation,
and apoptosis. ATP is the energy source for cellular metabolism, which means that mito-
chondria are essential for cell functioning. There are
100 mitochondria/cell. However, dif-
ferent cell types have differing energy needs so that they require differing numbers of mito-
chondria.
A.
Substrates are metabolized in the mitochondrial matrix to produce
acetyl CoA,
which is oxi-
dized by the tricarboxylic acid cycle to carbon dioxide.
B.
The energy released by this oxidation is captured by reduced nicotinamide adenine dinu-
cleotide (NADH) and flavin adenine dinucleotide (FADH
2
). NADH and FADH
2
are further
oxidized, producing
hydrogen ions
and
electrons
C.
The electrons are transferred along the
electron transport chain,
which is accompanied by the
outward pumping of hydrogen ions into the intermembrane space (
chemiosmotic theory
).
The electron transport chain includes the following enzymes: NADH dehydrogenase
(Complex I), succinate dehydrogenase (Complex II), ubiquinone-cytochrome c oxidoreduc-
tase (Complex III), and cytochrome oxidase (Complex IV).
D.
The
F
0
subunit of ATP synthase
forms a transmembrane hydrogen ion pore so that hydrogen
ions can flow from the intermembrane space into the matrix, where the
F
1
subunit of ATP syn-
thase
catalyzes the reaction
ADP
P
i
S
S
ATP.
II. THE HUMAN MITOCHONDRIAL GENOME
A.
The mitochondrial genome is completely separate from the nuclear genome. In this regard,
transcription of mitochondrial DNA (mtDNA) occurs in the mitochondrial matrix, whereas
transcription of nuclear DNA occurs in the nucleus.
B.
The replication of mtDNA is catalyzed by DNA polymerase
, whereas the replication of
nuclear DNA is catalyzed by DNA polymerase
and .
C.
There are several copies of the genome per mitochondrion. The human mitochondrial
genome consists of mtDNA arranged as a
circular piece of double-stranded DNA (H strand
and
L strand
)
with 16,569 base pairs and is located within the
mitochondrial matrix.
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BRS Genetics
D.
In contrast to the human nuclear genome, mtDNA is not protected by histones (i.e.,
histonefree
).
E.
The human mitochondrial genome codes for
37 genes,
which make up
93% of the human
mitochondrial genome
.
There are
13 protein-coding genes
and
24 RNA-coding genes.
The fact
that the 37 genes make up
93% of the human mitochondrial genome means that
93% of
the human mitochondrial genome consists of coding DNA
and
7% of the human mitochondr-
ial genome consists of noncoding DNA
(compare with the human nuclear genome in
Chapter 1).
F.
All human mtDNA genes
contain only exons
(i.e., no introns are present).
A.
The protein-coding genes of the mitochondrial genome encode for 13 proteins that are not
complete enzymes but are
subunits of multimeric enzyme complexes
used in electron trans-
port and ATP synthesis. These 13 proteins synthesized on mitochondrial ribosomes.
B.
The 13 proteins include the following:
1.
7 subunits of the NADH dehydrogenase (i.e., ND1, ND2, ND3, ND4L, ND4, ND5, and ND6;
Complex I)
2.
3 subunits of the cytochrome oxidase (i.e., CO1, CO2, and CO3; Complex IV)
3.
2 subunits of the F
0
ATP synthase (i.e., ATP synthase 6 and ATP synthase 8)
4.
1 subunit (cytochrome b) of ubiquinone-cytochrome c oxidoreductase (i.e., CYB1;
Complex III)
A.
The RNA-coding genes of the mitochondrial genome encode for 24 RNAs.
B.
The 24 RNAs include:
1.
2 rRNAs (16S and 23S)
2.
22 tRNAs (corresponding to each amino acid)
V. OTHER MITOCHONDRIAL PROTEINS
All other mitochondrial proteins (e.g., enzymes of the citric acid cycle, DNA polymerase,
RNA polymerase) are
encoded by about 90 genes in the nuclear DNA, synthesized on cytoplas-
mic ribosomes,
and then
imported into the mitochondria.
The mutation rate of mtDNA is about ten times that of nuclear DNA because only limited
DNA repair mechanism exists in the mitochondrial matrix. This higher mutation rate may
also be related to free radical production during oxidative phosphorylation.
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