Name (Last)

(First)

Student ID

KEY

CM156/256 Midterm Exam II (February 23, 2015)

Circle your discussion section for return of the exam:
Alejandra
1
5

(30pts)
(10pts)

2
6

(20pts)
(10pts)

Millie
3
7

(10pts)
(5pts)

4
8

(5pts)
(10pts)

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.

Different mutations in the lamin A gene give rise to distinct diseases including
muscular dystrophy, familial lipodystrophy, and Hutchinson-Gilford progeria. This
is an example of:
i)
Pleiotropy
ii)
Reduced penetrance
iii)
Co-dominance
iv)
Variable expressivity
v)
Compound heterozygosity

B.

The BEST genetic evidence for the role of a gene in a dominant disorder is:
i)
Cosegregation of the disease and a SNP
ii)
Linkage disequilibrium
iii)
New mutation present in affected individual but not in parents
iv)
Chain termination mutation
v)
Amino acid substitution

C.

The table shows some linkage data for Waardenburgs syndrome. What is the most
likely distance between the marker and disease gene?
i) No significant linkage was observed
ii) More than 30 cM
Linkage of gene for Waardenburgs Syndrome to 2q37
iii) About 20 cM
Recombination fraction q
iv) About 10 cM
Family
0.00
0.05
0.10
0.20
0.30
0.40
v) About 5 cM
1
2.26
2.06
1.86
1.42
0.93
0.42

D.

What is an explanation for the

result in the above table with
family 5?
i) Locus heterogeneity
ii) Nonpaternity
iii) Genotyping error
iv) Chance
v) All of the above

2
0.96
0.88
0.80
0.62
0.44
0.23
3
1.15
1.00
0.84
0.53
0.24
0.05
4
1.45
1.28
1.10
0.73
0.36
0.09
5
-1.26
-0.55
-0.33
-0.14
-0.05
-0.01
Total
4.56
4.68
4.27
3.16
1.91
0.77
Values represent lod scores calculated for various genetic distances
(expressed as recombination fraction) from a genetic marker at 2q37

E.

In the recessive trait cystic fibrosis one allele accounts for about half of the mutant
copies in a large population. The other half consists of a large number of rare
mutations. What prediction can be made about the fraction of cystic fibrosis patients
with the possible different genotypes in that population?
i)
The largest fraction are compound heterozygotes with the common mutant
ii)
The largest fraction are homozygotes with the common mutant
iii)
The largest fraction are compound heterozygotes with rare alleles
iv)
The largest fraction are homozygotes with rare alleles
v)
Equal frequencies of compound heterozygotes and homozygotes

F.

How does inbreeding differ from pseudo-dominance as an explanation of disease

inheritance?
i)
Usually unaffected parents have affected children
ii)
Multiple sibs are affected
iii)
Parents often dont realize they share a common ancestor with the mutation
iv)
Disease manifestation may appear to skip a generation
v)
Affected-by-affected matings yield all affected children

G.

Classical medical diagnosis has used techniques such as Southern blotting, PCR, and
sequencing of candidate genes. As compared to these, which of the following is the
most significant advantage of using whole genome sequencing/exome sequencing?
i)
The causal gene does not need to be known a priori
ii)
The possibility of uncovering unknown consanguinity and nonpaternity
iii)
The identification of deleterious mutations in unintended targets such as
BRCA1 and BRCA2
iv)
Less expensive
v)
Possibility of identifying epigenetic disorders

H.

A GWAS study was posted with these results:

What is the odds ratio favoring allele A with

Allele A present
Allele A absent

Cases
600
300

Controls
400
400

cases?
i)
ii)
iii)
iv)
v)
I.

4.0
3.0
2.0
1.5
1.3

You are performing an association study in which you genotype 10,000 SNPs in
5000 controls and 5,000 cases. What would be an appropriate p-value for
significance?
i)
5x10-2
ii)
5x10-3
iii)
5x10-4
iv)
5x10-5
v)
5x10-6
2

J.

(20pts)

Shown below is Figure 2 from Wu et al. Which conclusion is supported by this

Figure?
i)
ADB1B GG produces more acetaldehyde
and ALDH GG clears acetaldehyde faster.
ii)
ADH1B GG allele produces less
acetaldehyde and ALDH GG clears acetaldehyde
faster.
iii)
ADH1B GG allele produces more
acetaldehyde and ALDH GG clears acetaldehyde
slower.
iv)
ADH1B GG allele produces less
acetaldehyde and ALDH GG clears acetaldehyde
more slowly.
v)
ADH1B GG allele and the ALDH GG allele do not affect acetaldehyde
levels.

2.
You type a series of microsatellite markers (with up to 8 alleles each, indicated by numbers
1-8) in the family below, with the following result.
IA

IB

IIA

IIB

markers
A
B
C
D
E
F
G

2
5
5
3
7
2
6

3
4
2
2
3
5
7

(3pts)

A.

3
8
2
4
1
5
7

3
4
2
2
3
5
7

2
5
5
3
7
2
6

4
5
3
6
7
5
6

IIIA

IIIB

3
4
2
2
3
5
7

3
4
2
3
7
2
6

IIIC
4
5
3
6
7
5
6

IIID
2
5
5
3
7
2
6

IIIE

3
4
2
2
3
2
6

4
5
3
6
7
5
6

IIIF
3
4
2
2
3
5
7

3
4
2
2
3
5
7

What aspects of this pedigree support X linked recessive inheritance?

Only males affected and all affected share same X-linked haplotype (unaffected
males in Generation III has most of unaffected grandfathers haplotype)

(3pts)

B.

Circle the informative meiotic products.

(3pts)

C.

Indicate (with a line between markers A-G) where all recombinations have occurred
in the informative meiosis.

(3pts)

D.

Which region of the genome (between which A-G markers) most likely contains the
disease gene?
C-F

(8pts)

E.

Calculate the lod score for linkage of marker D with the disease gene at a
recombination fraction () of 0.2 (just set up the equation).
log10

(0.8)4 (0.2)0
(0.5)4
3

(10pts)

3.

Shown above is Figure 1 of Parma et al (Week 5). The shading of the symbols indicates the
phenotypes of the family members:
(5pts)

A.

Why arent XX male and SCC as useful as PPK for linkage analysis?
Fewer subjects for recombination studies; sex change genotype can only be
detected in XX, not XY and SCC phenotype has lower penetrance, so mutant
genotype can be detected with fewer people

(5pts)

B.

How do the genotype data suggest that families A and F are due to different
mutations in R-spondin?
The R-spondin mutation core region shows different haplotype (markers) in the
two families A and F.

(5pts)

4.
Genome wide association studies have, in most cases, explained only a small fraction of the
estimated heritabilty of a disease despite the fact that many loci have been identified. What are two
possible explanations?
1)
Not all the common genes with smaller effects have been discovered
2)
Rare variants that might have large effects not discovered by chance for
these sample sizes
3)
Gene interactions not examined
4

(10pts)

5.
The data in Figure 4 (below) from Keramati et al. (Week 6) suggest that kinase activity of
DYRK1b is not required to increase G-6-phosphatase expression. Explain and circle the relevant
part of the figure from which they draw this conclusion.
The inactive (dead kinase protein)
allele DYRK1b Y271/273F induces G6-phosphatase when added to the assay
cells.

(10pts)

6.
LCAT is an enzyme involved in cholesterol metabolism in the blood. Suppose you find that
the levels of LCAT activity in the serum exhibit common variation in the human population.
(4pts) A.
You decide to sequence the LCAT gene exons of individuals with high levels and
low levels to test for structural variants that affect enzyme activity. You identify four
missense variants but no nonsense or splice-site mutations. How would you prioritize which
missense variants to first examine in experimental studies?
Highest priority to mutations in conserved residues or to likely deleterious mutations
where amino acid change changes protein shape, charge, or predicted activity or to
mutations found on SNPs in common database.
(3pts)

B.
After much work, you conclude that none of the missense variants contribute to the
LCAT activity variations. You therefore obtain some precious human liver samples from
which you can isolate RNA and find that LCAT mRNA levels vary in the population and
correlate with LCAT activity. You suspect that there may be a promoter or enhancer
variation in the LCAT gene that affects expression. To examine this, you decide to perform
RNA-Seq to test for allele specific expression. You sequence LCAT mRNA from several
individuals differing in LCAT mRNA levels and heterozygous for an A/G missense
polymorphism and find that there are about the same number of RNA sequence reads from
each allele (A or G). What can you conclude?
Both copies equally expressed so activity variation is not explained by cis acting
regulation

(3pts)

C.
You then examine LCAT activity levels in serum from several hundred individuals
and use association analysis to map the underlying locus. You find that LCAT activity maps
to a locus on Chromosome 5, whereas the LCAT gene resides on Chromosome 8. Propose a
possible explanation.
A transcription factor from chromosome 5 controls LCAT expression via trans regulation.
Different alleles of transcription factor explain LCAT activity variation
5

(5pts)

7.
How do the data in Figure 2a from Parma et al (Week 5) indicate the mutation is a base
insertion?
In the wt/- heterozygote the arrow marks
mostly an apparent heterozygosity start
which contains downstream. Indicates a
frameshift mutation there, either + or -.
In the -/- homozygote the arrow marks a
new G, present in the heterozygote but not
the wt/wt homozygote. Downstream has
the same sequence as the wt/wt starting at the original A nucleotide. Indicates the
frameshift mutation is a single G insertion.
8.

(10pts)

(4pts)

Shown below is a panel from Wu et al. Answer the following questions.

A.
What are the most likely candidate genes at the locus? Explain the basis of your
answer.
TMEM188, HEATR3 are most likely based on presence in the linkage
disequilibrium block with highest significance scores. Adjacent genes such as
2NF423, PAPD5, ADCY7, BRD7, etc., might be possible if the causal variant
linked to the identified SNPs is in an enhancer some distance from the candidate
gene.

(3pts)

B.
Based on the average number of genes per Mb in the human genome, is the region
from 48 to 49 Mb a gene dense or gene poor region? Explain.
Neither: 7 genes are indicated between 48.0 and 49.0 Mb.
The expressed number is ~20,000 genes ~ 6-7 genes/Mb
3,000 Mb

(3pts)

C.

Some of the SNPs in the figure are colored. What does this indicate?
The colors refer to the correlation strength between peak SNP with lowest P-value
and adjacent SNPs. The r2 heat code on the right lists the correlation values.
Correlated SNPs in the disequilibrium block suggests a unique causative
haplotype at this locus
6