Pharmacogenomics (Exam II Material) PHS 112

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Pharmacogenomics (Exam II Material) PHS 112
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Exam II Practice PHS 112 Pharmacogenomics
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  1. What does MGD stand for and what kind of a database is it?
    1. MGD stands for Mouse Genome Database (hosted by Trans-NIH Mouse Initiatives)

    2. MGD is an integrated data resource for mouse genetic, genomic, and biological information. MGD includes a variety of data, ranging from gene characterization and genomic structures to orthologous relationships between mouse genes and other mammalian species, to maps (genetic, cytogenetic, physical) to descriptions of mutant phenotypes, to characteristics of inbred strains, to information about biological reagents such as, clones and primers.
  2. What does BLAST stand for and what kind of a database is it?
    1. BLAST stands for Basic Local Alignment Search Tool.

    2. In bioinformatics, BLAST is an algorithm for comparing primary biological sequence information, such as the amino-acid sequences of different proteins or the nucleotides of DNA sequences. A BLAST search enables a researcher to compare a query sequence with a library or database of sequences, and identify library sequences that resemble the query sequence above a certain threshold.Different types of BLASTs are available according to the query sequences. For example, following the discovery of a previously unknown gene in the mouse, a scientist will typically perform a BLAST search of the human genome to see if humans carry a similar gene; BLAST will identify sequences in the human genome that resemble the mouse gene based on similarity of sequence.
  3. What kind of a database is PubMed?
    1. PubMed is a free search engine accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. The United States National Library of Medicine (NLM) at the National Institutes of Health maintains the database as part of the Entrez system of information retrieval. PubMed provides quality control in scientific publishing. Only journals that meet PubMed's scientific standards are indexed.
  4. What does OMIM stand for and what kind of a database is it?
    1. OMIM stands for Online Mendelian Inheritance in Man

    2. OMIM is a comprehensive, authoritative compendium of human genes and genetic phenotypes that is freely available and updated daily. The full-text, referenced overviews in OMIM contain information on all known mendelian disorders and over 12,000 genes. OMIM focuses on the relationship between phenotype and genotype. It is updated daily, and the entries contain copious links to other genetics resources.
  5. What does PharmGKB stand for and what kind of a database is it?
    1. PharmGKB stands for Pharmacogenomics Knowledge Base

    2. PharmGKB is responsible for the aggregation, curation, integration and dissemination of knowledge regarding the impact of human genetic variation on drug response. It is funded by the National Institutes of Health (NIH) National Institute of General Medical Sciences (NIGMS), and is a partner of the NIH Pharmacogenomics Research Network (PGRN). It has been managed at Stanford University since its inception in 2000.

    The main goal of PharmGKB is to aid researchers in understanding how variation in a person’s genetic makeup affects how he or she responds to a drug, a field known as pharmacogenomics or pharmacogenetics (PGx). In order to achieve this goal, PharmGKB manually curates PGx information from the primary literature, and then stores it in the knowledgebase. This information can be aggregated, allowing PharmGKB to identify consistent genetic variant-drug response interactions. Variant-drug interactions with a large amount of supporting evidence may then be considered for potential clinical implementation.
  6. Which database would be most useful for obtaining a quick, referenced summary of the literature on the genetics of human diseases? 

    A. MGD
    B. PubMed
    C. OMIM
    D. Blast
    e. None of the above
    C. OMIM

    (Online Mendelian Inheritance in Man)
    (this multiple choice question has been scrambled)
  7. What are restriction endonucleases and why are they useful in genetic studies?
    1. Restriction endonucleases are a class of enzymes that have the ability to cleave DNA at designated areas called restriction sites; they cleave phosphodiester bonds.

    • 2. The long chromosome-size DNA molecules of genomic DNA, must be cut into fragments of much smaller size before they can be inserted into a vector. Most cutting is done with the use of bacterial restriction enzymes. These enzymes cut at restriction sites, and this property is one of the key features that make restriction enzymes suitable for DNA manipulation.
    • With restriction enzymes having the ability to recognize specific cleavage sites, suspected sequences for illnesses can be cleaved and isolated for amplification in PCR applications.
  8. What is matrilineal inheritance? Can you give an example?
    1. Transmission from just the mother, but to children of either sex.

    2. The pattern of mitochondrial inheritance; mitochondrial DNA is only inherited through the mother.
  9. Can you name two important model organisms in genomics other than mice/rats and their specific uses?
    1. Flies (Ex. Drosphilia);The human genome contains 3-4 times as many genes but most of these are thought to have arisen by two rounds of genome doubling during the evolution of vertebrates. Therefore, humans have more genes than flies but about the same number of gene families. Since it is easy to create mutants and carry out experiments on fruit flies, the functions of many fly genes have been established. The relationship between fly and human genes is so close that the sequences of newly discovered human genes, including disease genes, can often be matched against their fly counterparts. This provides a lead towards the function of the human gene and could help in the development of effective drugs.

    2. Yeast (Ex. Sacchromyces spp.);The yeast genome is just over 12 million base pairs in length and contains about 6000 genes. Perhaps surprisingly, about 20 per cent of human disease genes have counterparts in yeast (see Comparative genomics ). This suggests that such diseases result from the disruption of very basic cellular processes, such as DNA repair, cell division or the control of gene expression .It also means that yeast can be exploited to look at functional relationships involving these genes, and to test new drugs. A yeast mutant that has lost the functional equivalent of a human disease gene can be screened with thousands of potential drugs in order to identify compounds that restore normal function to the yeast cell. These compounds, or molecules like them, might also be useful in humans.
  10. Describe the difference between an allele and a locus?
    1. an allele is the alternate form of a gene.

    2. a locus is the specific location of a gene.
  11. Define ortholog and paralog. In considering gene function why is the distinction between these two terms important?
    1. Orthologs are genes in different species that evolved from a common ancestral gene by speciation; either of two or more homologous gene sequences found in different species related by linear descent

    2. Paralogs are genes related by duplication within a genome; either of a pair of genes that derive from the same ancestral gene

    • Part (a) of the diagram above shows a hypothetical evolutionary history of a gene. The ancestral genome had two copies of this gene (A and B) which were paralogs. At some point, the ancestral species split into two daughter species, each of whose genomes contain two copies of the ancestral duplicated gene (A1,A2 and B1,B2). These genes are all homologous to one another but are they paralogs or orthologs? Since the duplication event that created genes. A and B occurred before the speciation event that created species 1 and 2, A genes will be paralogs of B genes and 1 genes will be orthologs of 2 A1 and B1 are paralogsA1 and B2 are paralogs.A2 and B1 are paralogs.A2 and B2 are paralogs.A1 and A2 are orthologs.B1 and B2 are orthologs
  12. 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?
    1. An inactivated and hence non-functional copy of a gene.

    2. duplication - modifications (mutations, insertions, deletions, frame shifts) to the DNA sequence of a gene can occur during duplication. These disablements can result in loss of gene function at the transcription or translation level (or both) since the sequence no longer results in the production of a protein. Copies of genes that are disabled in such a manner are termed non-processed or duplicated pseudogenes.

    retrotransposition - reverse transcription of an mRNA transcript with subsequent re-integration of the cDNA into the genome. Such copies of genes are termed processed pseudogenes. These pseudogenes can also accumulate random disablements over the course of evolution.
  13. 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 ‘Huntington’ located at 4p16.3. What is Huntington’s chromosomal location?
    1. Huntington's is on chromosome 4; petite (short) arm; region 1; subunit 6.3
  14. 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?
    1. Recessive traits cause a loss of function—therefore, metabolizing enzymes, or proteins associated with metabolizing enzymes, cease to function properly or are greatly reduced due to errors/mutations to the genes involved in their development.

    2. With dominant traits, you gain a function. Activity is increased due to increased or enhanced binding of substrate.
  15. Briefly describe DNA microarrays. Describe one potential use in the pharmaceutical sciences.
    1. A microarray (also commonly known as DNA chip or biochip) is a collection of microscopic DNA spots attached to a solid surface. Scientists use DNA microarrays to measure the expression levels of large numbers of genes simultaneously or to genotype multiple regions of a genome; oligonucleotides or cDNA clones fixed on a glass surface. They are commonly used in a form of reverse hybridization assay to test for sequence variation in a known gene, or to profile gene expression in an mRNA preparation.

    2. Microarrays can be used in pharmaceutical applications to characterize and validate new therapeutic targets, their mechanism of action, metabolic pathways and unwanted secondary effects.
  16. What are CpG dinucleotide islands and why are they useful in gene discovery?
    1. CpG is shorthand for "—C—phosphate—G—", that is, cytosine and guanine separated by only one phosphate; phosphate links any two nucleosides together in DNA. CpG islands are short stretches of DNA, often <1 kb, containing frequent unmethylated CpG dinucleotides. CpG islands tend to mark the 5′ ends of genes.2. Many genes in mammalian genomes have CpG islands associated with the start of the gene (promoter regions). Because of this, the presence of a CpG island is used to help in the prediction and annotation of genes.
  17. 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?
    The SNP, in this case, does not change the amino acid sequence but changes the codon sequence ultimately slowing down the translation results in mRNA stability.

    A substitution may be synonymous with this SNP because a silent-type substitution may be linked to a polymorphism
  18. 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. (Ex Codeine is metabolized to morphine; active form)
    1. A genetic polymorphism in metabolizing enzymes may inhibit or greatly reduce the conversion of a prodrug into its active form, significantly limiting its therapeutic effects.

    2. Likewise, a genetic polymorphism can also increase the serum levels of a drug that may already be in its active form, and needs to be metabolized to become inactive—leading to toxicity. (Ex. Warfarin is metabolized to hydroxylated metabolites; the inactive form)
  19. 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?
    • they are determined by the
    • interplay of several genes encoding proteins
    • involved in multiple pathways of drug metab-
    • olism, disposition, and  

    • This study assumes that drug toxicity is determined by nonspecific effects or through receptors that do not exhibit functionally important genetic polymorphisms, although clearly toxicity can also be determined by genetic polymorphisms in
    • drug receptors. Thus, the individual with homozygous wild-type drug-metabolizing enzymes and drug receptors would
    • have a high probability of therapeutic efficacy and a low probability of toxicity, in contrast to an individual with homozygous mutant genotypes for the drug-metabolizing enzyme and the drug receptor, in which the likelihood of efficacy is low and that of toxicity is high.
  20. 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.
    The nomenclature for the CYP2C9 SNPs is unique: the normal, or wild-type, variant is referred to as *1 ("star 1"), the two polymorphic versions are *2 ("star 2") and *3 ("star 3"), and each person can carry any two versions of the SNP.

    I would suspect that *3 being a mutant type, would decrease or increase drug metabolism depending on the type of mutation. Either way, the *1 allele is the wild-type there by indicating a normal response.
  21. Briefly describe the function/utility of the following databases/resources available at the National Center
    for Biotechnology Information (NCBI).

    OMIM–
    Blast –
    Human Map Viewer –
    OMIM– Online Mendelian Inheritance in Man (compendium of human genes and genetic phenotypes)

    Blast – Basic Local Assignment Search Tool (enables a researcher to compare a query sequence with a library or database of sequences above a certain threshold)

    Human Map Viewer – An interactive viewer of physical and genetic maps, genomic sequence, genes, and other genomic annotations.
  22. Please briefly describe the polymerase chain reaction (PCR) and give two examples of its importance in
    the pharmaceutical sciences.
    1. PCR is a means of amplifying many copies of DNA (or RNA) from a single copy of genetic material.

    2. PCR is helpful in monitoring DNA during treatments for Hepatitis B.
  23. Distinguish between paralog and homolog genes. Why is the distinction important in gene studies? Please explain whether a pseudogene can be a homolog.
  24. The traditional model organism for the study of biochemical pathways is:

    A. Drosophila
    B. Zebra Fish
    C. C. elegans
    D. Mouse
    E. None of the above
    E. None of the above
  25. In paper by Phillips et al. titled “Potential role of pharmacogenomics in reducing adverse drug the 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?
  26. 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.
  27. What is the difference between an allele and a locus?
    1. an allele is the alternate form of a gene.

    2. a locus is the specific location of a gene.
  28. What is Heteroplasmy?
    The situation in which, within a single cell, there is a mixture of mitochondria (energy producing cytoplasmic organelles), some containing mutant DNA and some containing normal DNA

    In other-words, an organelle containing multiple mitochondrial DNA.
  29. Can you name two important model organisms in genomics other than mice/rats and their specific uses?
    1. C. elegans - important in nervous system studies. There is a complete wiring diagram of the nervous system: 302 neurons and the connections between them are known.

    2. Fruit Fly (Drosphilia) - used as a model organism for gene function.
  30. 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.
    1. Pseudogenes are dysfunctional relatives of genes that have lost their protein-coding ability or are otherwise no longer expressed in the cell. Pseudogenes often result from the accumulation of multiple mutations within a gene whose product is not required for the survival of the organism.

    2. Yes. If these pseudogenes are present in a human, it would be possible that there is a functional ortholog present in a rat. The genes may have common ancestry which have diverged and are no longer functional in humans.
  31. 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?
    1. retrotransposition - reverse transcription of an mRNA transcript with subsequent re-integration of the cDNA into the genome. Such copies of genes are termed processed pseudogenes. These pseudogenes can also accumulate random disablements over the course of evolution.

    2. Stop codons or frameshifts mid-sequence would lead me to believe this was a result of a retrotransposition.
  32. 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?
    1. MGD - Mouse Genome Database; an integrated data resource for mouse genetic, genomic, and biological info.

    2. PharmGKB - Pharmacological Knowledge Base; a database of aggregated, curated, and integrated knowledge of human genomic variation on drug response.

    3. BLAST - Basic Local Assignment Tool; used for comparing primary biological sequence information such as amino acids and proteins or nucleotides of DNA sequences.

    4. OMIM - Online Mendelian Inheritance in Man; an authoritative compendium  of humane gens and genetic phenotypes, freely available and updated daily.
  33. Choose two of the model organisms below and describe what system or process the organism is a model for and why. 

    1. Fruit fly
    2. Caenorhabditis elegans
    3. Mouse/Rat
    4. Zebra fish
    5. Yeast
    6. E. coli
    1. Fruit Fly - Used as a model system for exploring gene function and identifying interacting partners of genes which have direct relevance to human systems.

    2. C. elegans - Nervous system. There is a complete wiring diagram of the nervous system: all 302 neurons and the connections between them are known. C. elegans also possesses genes for most of the known molecular components of vertebrate brains.

    • 3. mouse - ability to construct mice with pre-determined genetic modifications to the germline (by transgenic technology and gene targeting in embryonic stem cells) has been a powerful tool in studying gene expression and function and in creating mouse models of human disease
    • Rat - mammal of choice for physiological, neurological, pharmacological and biochemical analysis.

    4. zebrafish - is a good model of vertebrate development

    5. Yeast - have a high frequency of nonhomologous recombination, it has been very amenable to genetic analysis, and a large amount of information was known about its gene structure, regulation and functionSome essential cellular functions, such as DNA repair, have been conserved between human and yeast cells, and as a result, yeast cells have provided useful models for understanding such processes.

    6. E. coli - studied, both biochemically and genetically, and was therefore an early priority for the Human Genome Project. The full genome sequence was released in 1997 but since then there have been a very large number of other prokaryotic genome projects, many of which have been completed already, including many pathogenic organisms
  34. 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
  35. MDR1 (ABCB1) is located on the short arm of chromosome 7 in region 2, subregion 1. How would you write this chromosomal location?
    7p21
  36. What are dynamic mutations? Can you give an example?
    Dynamic mutations are those caused by the expansion of existing polymorphic DNA repeat sequences beyond a copy number threshold. These genetic mutations can give rise to dominant, recessive or X-linked disorders, dependent upon the location of the repeat sequence with respect to the genes that are affected by the expansion. The distinguishing feature of these mutations is their instability, which is a function of the copy number of repeats and can occur in either meiosis or mitosis.

    Examples of diseases include: Huntington's disease (HD), spinobulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), a number of spinocerebellar ataxias (SCAs), oculopharyngeal muscular dystrophy (OPMD), myotonic dystrophy Type 1 and 2 (DM1 and 2), Huntington's disease-like 2 (HDL-2), Friedrich's ataxia (FRDA), Fragile X associated tremor ataxia syndrome (FXTAS), Fragile XE (FRAXE) and Fragile XA (FRAXA)
  37. Define dosage-sensitivity. Can you give two examples of the types of genes you would expect to exhibit dosage sensitivity?
  38. 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) DNA microarray.
    C) Real Time PCR
    D) Western blot
    A) Restriction enzymes - are DNA-cutting enzymes found in bacteria (and harvested from them for use). Because they cut within the molecule, they are often called restriction endonucleases.

    B) Real Time PCR

    C) Western blot - This method is designed to survey gross protein expression using cell extracts which are fractionated according to size

    D) DNA microarray - (1) A microarray (also commonly known as DNA chip or biochip) is a collection of microscopic DNA spots attached to a solid surface. Scientists use DNA microarrays to measure the expression levels of large numbers of genes simultaneously or to genotype multiple regions of a genome; oligonucleotides or cDNA clones fixed on a glass surface. They are commonly used in a form of reverse hybridization assay to test for sequence variation in a known gene, or to profile gene expression in an mRNA preparation. (2) Microarrays can be used in pharmaceutical applications to characterize and validate new therapeutic targets, their mechanism of action, metabolic pathways and unwanted secondary effects.
    (this multiple choice question has been scrambled)
  39. Many authors (including our textbook) make a distinction between Drug Metabolism or Transport Pharmacogenetics and Drug Target Pharmacogenetics. Can you describe the difference?
  40. Why do pseudogenes often occur in clusters along with similar functional genes?
  41. Define any 2 of the following:

    1. Compound heterozygote
    2. Dominant-negative mutations
    3. Diplotypes
    4. Haploinsufficiency
    1. Compound heterozygote - The presence of two different mutant alleles at a particular gene locus, one on each chromosome of a pair

    2. dominant-negative mutation - a mutation whose gene product adversely affects the normal, wild-type gene product within the same cell, usually by dimerizing (combining) with it. In cases of polymeric molecules, such as collagen, dominant negative mutations are often more deleterious than mutations causing the production of no gene product (null mutations or null alleles)

    3. diplotype - a combination of two haplotypes

    4. Haploinsufficiency - occurs when a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy does not produce enough of a gene product (typically a protein) to bring about a wild-type condition, leading to an abnormal or diseased state. It is responsible for some but not all autosomal dominant disorders.
  42. What sort of inheritance pattern (recessive, dominant, co-dominant) would you expect neomorph mutations to exhibit? Why?
    A neomorph is a structure that is not derived from a similar structure in an ancestor;  a mutant gene having a function distinct from that of any nonmutant gene of the same locus.

    This would be an example of a dominant trait. Any mutation that leads to the development of new functions, is a dominant (the opposite would be loss of a function, recessive).
  43. True or False: It is possible for a gene to be functional in some human populations and a pseudogene in other populations?
    True
  44. 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?
  45. 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. Missensemutations
  46. Human CYP2C19, an important in drug metabolizing enzyme, is located on the 10th chromosome, long arm, region 2, subregion 4. In chromosomal nomenclature how is this designated?
    10q24
  47. 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.
    An ortholog is the result of genes that diverged after a speciation event. The genes generally maintain a similar function (although variations may arise) to the ancestral gene.
  48. 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.
    1. Polygenomic drug targeting

    2. Genotype specific dosing

    3.
  49. 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?
  50. 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?
    How we metabolize drugs in regards to polymorphisms will depend on whether the drug is a prodrug (inactive) or in its active form. 

    If the patient is a "poor metabolizer", the patient can hypothetically have a reduced functioning CYP enzyme towards a prod-drug, where the pro-drug will not be metabolized to its active form (i.e. inactive codeine ---> active morphine). 

    Conversely, this same patient may be a poor metabolizer to certain prodrugs, but an Ultra rapid metabolizer to certain ACTIVE drugs, such as warfarin, which need to be metabolized by CYP enzymes to be inactivated. Otherwise, the drug will build up in serum to toxic levels.
  51. 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?
    1. Orthologous genes are homologous genes that diverged after a speciation event. The genes generally maintain a similar function to that of the ancestral gene in which they evolved from. In this type of homologous gene, the ancestral gene and its function is maintained through a speciation event, though variations may arise within the gene after the point in which the species diverged.

    2. Paralogous genes are homologous genes that occur within one species and have diverged after a duplication event. Unlike orthologous genes, a paralogous gene is a new gene that holds a new function. These genes arise during gene duplication where one copy of the gene receives a mutation that gives rise to a new gene with a new function, though the function is often related to the role of the ancestral gene.
  52. 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?
  53. 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?
    Huntington's chromosomal location is located on chromosome 4, petite arm, region 1, subunit 6.3.
  54. 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?
    Thiopurines are most commonly used to treat nonmalignant conditions but are also critical anticancer agents. The approach to dosing adjustments based on TPMT status may differ depending on the clinical indication and the propensity to initiate therapy at higher vs. lower starting doses. We and others advocate testing for TPMT status prior to initiating thiopurine therapy, so that starting dosages can be adjusted accordingly.

    • Three thiopurines are used clinically: azathioprine (a prodrug for MP), MP, and thioguanine. Although all three medications share many of the same pharmacologic effects,
    • MP and azathioprine are used for nonmalignant immunologic disorders, MP for lymphoid malignancies, and thioguanine for
    • myeloid leukemias.

    • Because azathioprine is a prodrug for MP, the two drugs can be considered to have identical interactions with TPMT; that is, TPMT catabolizes MP to inactive methylMP, leaving less parent drug available for eventual anabolism to active TGNs. The secondary metabolite of MP, TIMP, is also a substrate for TPMT, and methylTIMP (and further phosphorylated metabolites, methylMP nucleotides or MeMPN) have some activity (mostly immunosuppressive and hepatotoxic); they inhibit de novo purine synthesis and may contribute to some of the adverse effects of thiopurines. Individuals who inherit two nonfunctional TPMT alleles are at 100% risk for life-threatening myelosuppression, due to high TGNs, if they receive chronic therapy with conventional doses of MP (or azathioprine). Despite having higher TGNs than wild-type
    • homozygotes, only ~30–60% of patients who are heterozygous for TPMT are unable to tolerate full doses of MP or azathioprine.
    • Some heterozygotes may have good thiopurine tolerance because they have lower concentrations (and thus fewer toxic effects) of the methylMP nucleotides (MeMPN) than do homozygous wild-type carriers, thereby allowing tolerance of higher TGNs. There is therefore more debate over the dosing of azathioprine and MP in patients who are heterozygous for TPMT as compared with those who are homozygous deficient, although heterozygotes are at significantly higher risk for toxicity than wild-type patients.

    • Although there is lower affinity between thioguanine and TPMT than between MP and TPMT, TPMT has a significant impact on the pharmacokinetics of thioguanine and thereby
    • on its therapeutic effects. Thioguanine is directly inactivated by TPMT to its inactive methylthioguanine base, leaving less of the drug available for anabolism to active TGN metabolites. There is no analogous secondary metabolite of thioguanine that can undergo activation through TPMT (i.e., there are no methyl-TIMP or methylMP nucleotides); as a result, patients receiving thioguanine are able to tolerate substantially higher TGN concentrations than are those receiving MP or azathioprine.
  55. 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?
    1. The duplication or amplification of the active CYP2D6 gene.

    2. An mutation that would cause someone to be an Ultra-Rapid Metabolizer, would be a gain of function mutation, meaning that it is a dominant trait. With that said, 50% of her offspring would be UR-metabolizers regardless of sex.
  56. 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.
    An ortholog is the result of genes that diverged after a speciation event. The genes generally maintain a similar function (although variations may arise) to the ancestral gene.

    I would run a BLAST analysis to identify library sequences that resemble the query sequence of a certain threshold.
  57. 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?
  58. 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?
    1. A frameshift mutation is a mutation that alters the normal translational reading frame of a mRNA by adding or deleting a number of bases that does not result in a multiple of three. (examples i.e. Cystic Fibrosis and Tay-Sachs)

    2.

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