Exam II Practice PHS 112 Pharmacogenomics
*Don’t forget to study the genomic mapping study questions from Exam I*
1) Which database would be most useful for obtaining a quick, referenced summary of the
literature on the genetics of human diseases?
a. MGD
b. Blast
c. PubMed
d. OMIM
e. None of the above
2) What are restriction endonucleases? Why are they so useful for molecular genetic studies?
3) Please answer any four of the following questions:
a. What is matrilineal inheritance? Can you give an example?
b. Can you name two important model organisms in genomics other than mice/rats and their
specific uses?
c. Describe the difference between an allele and a locus?
d. Define ortholog and paralog. In considering gene function why is the distinction between these
two terms important?
4) The members of the gene family CYP2D are clustered on chromosome 22. The cluster
contains the functional gene CYP2D6 and 2 or 3 highly homologous pseudogenes? What are
pseudogenes? How do they arise in the genome?
5) Huntington disease (HD) is inherited as an autosomal dominant disease that gives rise to
progressive, selective (localized) neural cell death associated with choreic movements and
dementia. The disease is associated with increases in the length of a CAG microsatellite triplet
present in a gene called ‘huntingtin’ located at 4p16.3. What is huntingtin’s chromosomal
location?
6) CYP2D6 polymorphism, which is responsible for the variation in metabolism of debrisoquine
4-hydroxylase, is important in the metabolism of more than 30 drugs and environmental
chemicals, including as much as 20% of all commonly prescribed drugs. CYP2D6 activity
ranges from complete deficiency to ultrafast metabolism, depending on at least 16 different
known alleles. Deficiencies in CYP2D6 activity are generally expressed as autosomal recessive
traits. In contrast, the ultrafast metabolizer phenotype (caused by gene duplication of up to 12
copies) is autosomal dominant. Please explain why these two classes of mutations exhibit
different patterns of genetic expression?
7) Briefly describe DNA microarrays. Describe one potential use in the pharmaceutical sciences.
8) What are CpG dinucleotide islands and why are they useful in gene discovery?
9) A SNP variant in the gene MDR1 has been shown to be correlated with reduced gene
expression levels.
However, the SNP results in a synonymous substitution. Can you provide an explanation for this
finding?
10) There are several drug metabolizing enzymes that have well described genetic
polymorphisms with clinical consequences. In general terms, provide two potential ways in
which a functional genetic polymorphism may affect the outcome (efficacy or toxicity) of drug
therapy.
11) In the paper by Evans and Relling titled “Pharmacogenomics: Translating Functional
Genomics into Rational Therapeutics” (Science 286:487-491) the authors note that “the overall
effects of medications are typically not monogenic traits”. What do they mean by this statement
and what does this mean in terms of phenotypic outcomes?
12) Phenytoin is a CYP2C9 substrate that is commonly administered to critically ill patients
following head trauma. Dr. Brad Boucher and others have described a clinically important
induction of phenytoin metabolism that occurs following head trauma. If trauma patients were
genotyped for CYP2C9, would you expect a greater induction of drug metabolism in a
homozygous CYP2C9*1 or a homozygous CYP2C9*3 genotype? Explain your choice.
13) Briefly describe the function/utility of the following databases/resources available at the
National Center for Biotechnology Information (NCBI).
a. OMIM –
b. Blast –
c. Human Map Viewer –
14) Please briefly describe the polymerase chain reaction (PCR) and give two examples of its
importance in
the pharmaceutical sciences.
15) Distinguish between paralog and homolog genes. Why is the distinction important in gene
studies?
Please explain whether a pseudogene can be a homolog.
16) The traditional model organism for the study of biochemical pathways is
a. Drosophila
b. Zebra Fish
c. elegans
d. Mouse
e. None of the above
17) In the paper by Phillips et al. titled “Potential role of pharmacogenomics in reducing adverse
drug reactions” (JAMA 286:2270-2279) the authors distinguish between adverse drug reactions
and adverse drug events.
a. In what way do they distinguish the two?
b. What was the major conclusion of their study and how did they support that conclusion?
18) While Caenorhabditis elegans has four semaphorin genes among its 20,000 genes, humans
have around 20 in a genome of about ~40,000 genes. Describe the mechanisms that could
explain this discrepancy. There are at least two.
19) What is the difference between an allele and a locus?
20) What is Heteroplasmy?
21) Can you name two important model organisms in genomics other than mice/rats and their
specific uses?
22) There are two pseudogenes very similar in sequence to CYP3A4 located on human
chromosome 7.
What are pseudogenes and how do they arise in the genome?
Is it possible for there to be a functional homologs to these pseudogenes in the rat genome?
Please explain.
23) In “Implications of the human genome for understanding human biology and medicine” by
Subramanian, Adams, Venter, and Broder the authors note the importance of retrotransposition
as one of the more important mechanisms of gene duplication. What is retrotransposition?
What feature of the sequence of a duplicated gene would lead you to suggest that this duplication
was the result of retrotransposition?
24) There are numerous databases on the Internet containing genomic information and human
disease/drug response. For example, dbSNP at the National Center for Biotechnology
Information (NCBI) is a database containing information on single nucleotide polymorphisms in
the human genome. Can you name and describe three other databases that we have discussed in
class?
25) Choose two of the model organisms below and describe what system or process the organism
is a model for and why.
Fruit fly
Caenorhabditis elegans
Mouse/Rat
Zebra fish
Yeast
E. coli
26) Polymorphisms in transporter genes may be expected to cause
a. No change in phenotype
b. Increased ability to transport substrates across plasma membrane
c. Transport of new substrates
d. All of the above
27) MDR1 (ABCB1) is located on the short arm of chromosome 7 in region 2, subregion 1. How
would you write this chromosomal location?
37) What are dynamic mutations? Can you give an example?
38) Define dosage-sensitivity. Can you give two examples of the types of genes you would
expect to exhibit dosage sensitivity?
39) Briefly describe any two of the following molecular tools AND also state for each at least
two applications in Pharmaceutical sciences of the techniques you chose.
A) Restriction enzymes
B) Real Time PCR
C) Western blot
D) DNA microarray.
40) Many authors (including our textbook) make a distinction between Drug Metabolism or
Transport Pharmacogenetics and Drug Target Pharmacogenetics. Can you describe the
difference?
41) Why do pseudogenes often occur in clusters along with similar functional genes?
42) Define any 2 of the following:
a. Compound heterozygote
b. Dominant-negative mutations
c. Diplotypes
d. Haploinsufficiency
43) What sort of inheritance pattern (recessive, dominant, co-dominant) would you expect
neomorph
mutations to exhibit? Why?
44) True or False: It is possible for a gene to be functional in some human populations and a
pseudogene in other populations?
45) CpG dinucleotide islands occur infrequently throughout the genome and are correlated with
coding regions.
a. How do CpG islands arise?
b. Would you also expect CpG islands to be correlated with regulatory regions? Why or Why
not?
46) Please describe the following mutations. Please include in your descriptions where these
mutations generally occur (coding, non-coding, intron, exons, and regulatory regions).
a. Frame shift mutations
b. Cryptic splice site mutations
c. Missense mutations
47) Human CYP2C19, an important in drug metabolizing enzyme, is located on the 10
chromosome, long arm, region 2, subregion 4. In chromosomal nomenclature how is this
designated?
48) The mouse gene, CYP2C65 is believed to be the ortholog of the human CYP2C19 gene.
What is meant by this statement and suggest ways one might confirm that human CYP2C19 and
mouse CYP2C65 are orthlogs.
49) To date, very few drugs have been required to contain information concerning
pharmacogenetics in their FDA-approved labeling. The FDA and the pharmaceutical industry are
attempting to define when pharmacogenetic data may be required from the industry for inclusion
in the labeling of a drug. Provide three examples of where you believe it will be logical for
pharmacogenetic data to be required by the FDA as a component of a drug’s labeling.
50) A 40 year-old man develops deep venous thrombosis in his right lower leg after a
transatlantic flight to the U.S. from his homeland, Nigeria. His past medical history is otherwise
significant for hypertension, borderline diabetes for which he does not take any medication and a
recent change to a vegetarian diet. While in the U.S. he is started on warfarin at a daily dose of 5
mg. It is subsequently determined over the ensuing 5 weeks that an increase in his daily dose to 9
mg is required in order to reach and maintain a therapeutic INR level a. What pharmacogene is
currently recognized to be the most important pharmacokinetic determinant in establishing and
maintaining a therapeutic warfarin dosing regimen.
b. What type of SNP – coding or non-coding – likely contributes to this patient’s insensitive
warfarin metabolizer phenotype?
c. What type of non-genetic pharmacokinetic factor - CYP450 enzyme inducer or inhibitor - may
contribute to this patient’s relatively resistant response to warfarin treatment?
d. What is the mostly likely pharmacodynamically-related genotype in this patient – VKORC1
A/A, A/B, or B/B?
e. What non-genetic pharmacodynamic factor - preexisting hypertension, borderline diabetes or
diet - most likely contributes to this patient’s relatively resistant response to warfarin treatment?
51) For some drugs CYP2D6 poor metabolizers (PM) show no benefit from taking the drug
while for other drugs CYP2D6 PMs suffer adverse reactions (toxicities). Can you provide an
explanation how the same variants (PMs) can have opposite effects with different drugs?
52) Many authors make a distinction between Drug Metabolism or Transport Pharmacogenetics
and Drug Target Pharmacogenetics. Can you describe the differences between the two AND
provide an example of each?
53) The phenotypic variance associated with the pharmacogenetics of drug transporters are often
far greater than the range of phenotypes seen in the pharmacogenetics of drug metabolizing
enzymes. Can you explain why this might be so?
54) Huntington disease (HD) is inherited as an autosomal dominant disease that gives rise to
progressive, selective (localized) neural cell death associated with choreic movements and
dementia. The disease is associated with increases in the length of a CAG microsatellite triplet
present in a gene called ‘huntingtin’ located at 4p16.3. What is huntingtin’s chromosomal
location?
55) You have taken a job as a pharmacist in Pig Butte, Arkansas (just south of Pig Snout, AK)
and a patient comes to you with a question about the pharmacogenetics of therapy with
mercaptopurine (6 MP) for childhood acute lymphoblastic leukemia (ALL). What would you tell
her?
56) A small percentage of the population can be classified as Ultra-rapid metabolizers (UM) of
CYP2D6 substrates. Please describe one possible molecular mechanism that would cause this
phenotype?
If a women who is an ultra-rapid metabolizer is married to a normal male (EM phenotype). What
proportion of their children will be phenotypically UM?
57) The mouse gene, CYP2C65 is believed to be the ortholog of the human CYP2C19 gene.
What is meant by this statement and suggest ways one might confirm that human CYP2C19 and
mouse CYP2C65 are orthlogs.
58) Briefly describe silencing RNA technologies (3 pts). There are some major problems that
must be solved before siRNAs can become therapeutic agents. Can you describe two problems?
59) Choose two of the model organisms below and describe what system or process the organism
is a model for and why.
Fruit fly Caenorhabditis elegans Mouse/Rat Zebra fish Yeast E. coli
60) What is a frame shift mutation and how do they arise?
Phenotypically, frame shift mutations and nonsense mutations in the same gene can give rise to
allelic heterogeneity. Can you provide an explanation for this?