Name (Last)

(First)

Student ID

KEY

CM156/256 Midterm Exam I (February 2, 2015)

Circle your discussion section for return of the exam:
Alejandra
1
6

(30pts)
(10pts)

2
7

(10pts)
(10pts)

Millie
3
8

(10pts)
(5pts)

4
9

(10pts)
(10pts)

(5pts)

Show your work for full credit. Include only information pertinent to the question.
(30pts)

1.

Select the best answer for each of the following questions:

A.

You have identified a child with Beckwith-Wiedemann Syndrome. You suspect the
cause is due to a small (<10kb) deletion on chromosome 11. How would you
confirm this?
i)
Chromosome painting
ii)
Exome sequencing
iii)
ChIP
iv)
Chromosomal microarray
v)
Karyotyping

B.

Jack and Jill were introduced to each other as having (unrelated) grandfathers with
albinism, a rare recessive condition. They plan to start a family. Hank and Hanna
who are first cousins, also plan to start a family. No other cases of albinism are
known for their families. Which couple has a higher risk of their first child having
albinism?
i)
Jack and Jill
ii)
Hank and Hanna
iii)
Equal risk = 1/8
iv)
Equal risk = 1/16
v)
Cannot determine

C.

Traditional gene targeting using homologous recombination and CRISPR/Cas9 are

both useful techniques to introduce specific modifications into the mammalian
genome. For the potential correction of mutations in human disease, CRISPR may be
more useful because it:
i)
Allows specific point changes in the genome
ii)
Produces permanent modification of protein coding sequences
iii)
Does not require the use of ES cells
iv)
Produces heritable changes in the genome
v)
Can be used to modify non-coding regions

D.

Which of the following statements about transgenic and gene targeting

technologies for engineering mice is NOT TRUE?
i)
Transgenes usually integrate into homologous regions.
ii)
The phenotype of transgenic mice varies more than that of gene targeted
mice.
iii)
Cre-loxP technology allows tissue specific gene targeting.
iv)
Gene targeting generally requires positive or negative selection.
1

v)

Gene targeting usually results in chimeric progeny.

E.

You perform FISH for XIST RNA and observe the results shown below. What is the
probably karyotype?
nucleus
i)
46, XY
ii)
47, XXY
iii)
48, XXXY
iv)
48, XXXX
v)
45, XO

F.

Which of the following is not a characteristic of imprinted genes?

i)
Parthenogenetic embryos are not viable in mice due to imprinted genes
ii)
DNA is often hypermethylated in imprinted genes.
iii)
Gametogenesis establishes new sex-specific imprint patterns.
iv)
Uniparental disomy in imprinted genes can lead to genetic diseases.
v)
Imprinting is constant across developmental stages and tissue types

G.

Which of the following is NOT TRUE about common disorders such as

schizophrenia and cancer?
i)
They are often due to multiple genetic and environmental factors
ii)
They frequently exhibit significant differences between sexes
iii)
It is possible to estimate the relative importance of genetics versus
environment
iv)
If one monozygotic twin develops a common disease, the other will almost
certainly also develop the disease
v)
The frequencies of different common diseases differ between ethnic groups

H.

Which of the following statements about mutations is NOT TRUE?

i)
Polymorphisms in the human population tend to be old
ii)
Mutations can be caused by radiation, by chemical damage, and by
errors during DNA replication
iii)
Dominant disease mutations are generally removed more rapidly by
selection than recessive disease mutations
iv)
During gametogenesis, more point mutations occur during
oogenesis than spermatogenesis
v)
Numerous new mutations are introduced into the germline every
generation.

I.

Phenylketonuria (PKU) among Yemenite Jews is caused by a deletion of the third

exon of the phenylalanine hydroxylase gene. The mutation is unique to the
population and is not found in the more numerous Moslem populations in Yemen nor
in other Jewish groups. This is most likely an example of:
i)
Selective advantage in heterozygotes
ii)
Selection caused by environment specific to that population
iii)
Founder effect
iv)
Inbreeding
v)
Linkage disequilibrium

J.

Suppose you have identified a mutation that confers resistance to HIV infection. You
wish to estimate how long ago the mutation occurred. For this, the most useful
information would be:
i)
The kind of mutation involved (missense, copy number, etc.)
ii)
Linkage disequilibrium at the locus
iii)
Microsatellite instability at the locus
iv)
The nature of the genes contained in the locus
v)
Genetic drift at the locus
3

(10pts)

2.
Deletion mapping of the Y-chromosome with a set of STS markers (A-E) was performed by
testing for the presence or absence of specific STSs by PCR in individuals known to have Ychromosome deletions. The results for analysis of XY males and females, as well as controls, are
shown below:
Individuals with Y deletions +
Control XY Male
Subjects

Markers

(5pts)

A
B
C
D
E

A.
Using data from the individuals, draw a map of the marker order along the Y
chromosome.
E

(5pts)

B.
Subjects 1 and 2 are XX males while the other subjects are XY females. What is
the most likely location of the SRY gene?
Near E

(10pts)

3.
The gene, OVWT (Overweight), has been shown to cause obesity in humans. You
hypothesize that this gene acts either to regulate appetite in the brain or to synthesize lipids directly
in fat cells. You have available a mouse strain that carries the modification in the endogenous mouse
Ovwt gene shown below. Briefly describe how you might use this mouse to determine whether
OVWT effect on body weight occurs in fat tissue or in the brain.

To check which tissue controls this system, generate tissue-specific Ovwt knockout mice
by expressing Cre in brain or in fat tissues independently
Brain Cre transgenic mice to remove OVWT expression
from brain
Fat cells Cre transgenic mice to remove OVWT
expression from fat cells

(10pts)

4.
In Long et al., CRISPR/Cas9 was used to repair a mutant Dmd gene in mouse by adding a
DNA template that contains the desired nucleotide alteration. Use of the same gRNA without
addition of the DNA template can result in the inactivation of the wild-type Dmd gene. Offer a
likely explanation.
gRNA brings Cas endonuclease to same site on Dmd to create a double strand break.
Without a template, repair will occur by non-homologous end joining, which often leads
to an insertion/deletion and inactivating frame-shift mutation in the Dmd gene.

(5pts)

5.
Suppose you examine alleles of the X-linked enzyme glucose-6-phosphate dehydrogenase
(G6PD) in normal female placentas of three families with the following results.
Father

G6PD
alleles

Family 1
Mother Daughter
placenta

Father

Family 2
Mother Daughter
placenta

Father

Family 3
Mother Daughter
placenta

1
2
What conclusion can you draw from this result?
Observation: Placenta of XX daughter expresses only mothers G6PD allele
Proposed explanation: Monoallelic expression due to X inactivation, and fathers X is
always inactive in the placenta

(10pts)

6.
A couple has two children with Prader-Willi syndrome. Cytogenetic analysis shows that one
of the parents carries a reciprocal translocation involving chromosome 15.
(4pts) A.
Is the translocation carried by the father or the mother?
Father
(6pts)

B.

What is the mechanism involved?

Father is normal because translocation is balanced all gene copies present.
Translocation can segregate unbalanced gametes, however, specifically gametes
missing the part of chromosome 15 distal to the breakpoint. This sperm creates
zygotes with only mothers copy of 15q, creates PWS.

(10pts)

7.
Shown below are SNP polymorphisms (1-6) that occur (in the order shown) in a 4kb region
of the X chromosome for ten different individuals (1-10).
SNP (allele)
(3pts)

A.

The minor allele frequency of SNP3 is:

i)
100%
ii)
75%
iii)
50%
iv)
40%
v)
20%

(4pts)

B.

Are SNPs 5 and 6 in linkage disequilibrium? Explain.

1
2
3
4
5
6
7
8
9
10

1
C
C
G
C
G
G
C
G
C
C

2
A
A
C
A
C
C
A
C
A
A

3
T
T
A
T
A
A
T
A
T
T

4
G
C
G
G
G
C
C
G
C
G

5
G
A
G
G
G
A
A
G
A
G

6
G
A
G
G
G
A
A
G
A
G

Yes, only G5G6 and A5A6 haplotypes observed instead of all 4 possible types

(3pts)

C.

Haplotype blocks are separated by so called recombination hotspots. The most

likely region for a recombination hotspot occurs between the following SNPs:
i)
1 and 2
ii)
2 and 3
iii)
3 and 4
iv)
4 and 5
v)
5 and 6

(5pts)

8.
The paper by Stelzer et al. (Week 3) deals with imprinting in Prader-Willi Syndrome. Figure
2C shows a set of genes that were quantitated in parthenogenic iPSC or Prader Willi iPSC. The
MEG3 gene shows the same expression levels in both cell types, whereas several of microRNA
genes show less expression in the parthenogenic as compared to Prader-Willi cell types. Propose an
explanation.
The microRNAs normally require paternally
expressed transcription factors for complete
expression. Most paternally expressed transcription
factors are present in PWS-IPSCs but are entirely
absent in PG-IPSCs (maternal copies only)

(10pts)

9.

Figure 4 from Tishkoff et al. (Week 4 reading paper) is shown below.

(4pts)

A.

What do the circles in Panel a represent?

Relative frequencies (%) of each haplotype

(6pts)

B.
What do the data presented in Panels a and b suggest about the origin of lactose
persistence in Africa versus Europe? Explain.
The T13910 (European) haplotype has a different origin from the (African) G13907 and other common resistant haplotypes.
1)
Separate pathways on the haplotype network and
2)
Different geographical distributions
8