CM156-Final-Winter 2023-Mar. 24-KEY

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1 Name (Last) (First) Student ID KEY CM156/256 Final Exam (March 21, 2023) BEFORE YOU BEGIN THE EXAM, circle your discussion teaching assistant: GABRIELLA LINDSEY 1. (54pts) 9. (5pts) 17. (15pts) 2. (4pts) 10. (5pts) 18. (10pts) 3. (4pts) 11. (4pts) 19. (6pts) 4. (6pts) 12. (10pts) 20. (5pts) 5. (15pts) 13. (5pts) 21. (6pts) 6. (5pts) 14. (10pts) 22. (5pts) 7. (10pts) 15. (5pts) 23. (5pts extra credit) 8. (5pts) 16. (6pts) Final Exam Total /200 pts Midterm Exam I /100 pts Midterm Exam II /100 pts Pop Quizzes /60 pts Discussion Section /140 pts Total /600 pts

2 (54 pts, 1. Indicate the best answer for each of the following multiple-choice questions 3pts each) A. What is the most likely phenotype of a female mouse heterozygous for a null mutation of XIST? i) Random inactivation of the two X chromosomes ii) The X chromosomes carrying the null XIST allele would remain active iii) The X chromosomes carrying the null XIST all allele would be inactivated iv) Lethal, as X chromosomes carry genes active on both copies in females v) None of the above B. Some differences that distinguish common diseases and Mendelian diseases include the following EXCEPT: i) Rare variants contribute to Mendelian disorders but not to common disease ii) The genetic contributions of individual chromosomal loci in common disease are small compared to Mendelian disease iii) Most of the causal variants in common diseases are in noncoding regions whereas in Mendelian diseases they are mainly in coding regions iv) The heritabilities of Mendelian diseases tend to be higher than those of common diseases v) Environmental factors tend to be more important for common disease than Mendelian diseases C. Genes associated with Prader-Willi syndrome are maternally imprinted. Which of the following scenarios at the locus will most likely lead to Angelman syndrome? i) Maternal deletion or maternal UPD ii) Paternal deletion or maternal UPD iii) Maternal deletion or paternal UPD iv) Paternal deletion or maternal UPD v) None of these combinations D. I want to detect whether a patient has a deletion in a unique 2000 bp region of a chromosome that I suspect is causing their phenotype. Which of the following would NOT be a technique that I could use to determine whether they have this deletion? i) FISH using probe for the region ii) G-banding karyotypes of cells in metaphase iii) Sequencing of the region iv) Comparative genomic hybridization of the region v) Loss of heterozygosity E. The table below shows lod scores calculated for 4 families exhibiting the disease. Lod score θ = 0 θ = 0.05 θ = 0.1 θ = 0.2 θ = 0.3 θ = 0.4 1 2.3 1.7 1.1 0.8 0.4 0.03 2 - ∞ 2.4 1.9 1.7 1.2 0.4 3 - ∞ -1.7 -1.0 -0.5 -0.1 0.1 4 - ∞ 3.1 2.4 1.8 1.2 0.4 The most likely distance between the marker and the disease gene is: i) 0 centimorgans ii) About 5 centimorgans iii) About 10 centimorgans iv) About 20 centimorgans v) The disease is not linked to the marker Note: This question was discarded for the exam

3 F. Cancers often improperly turn on telomerase expression. This would result in the following property: i) Self-sufficiency in growth signals ii) Insensitivity to anti-growth signals iii) Apoptosis avoidance iv) Limitless replicative potential v) Tissue invasion G. Genetic counseling for breast cancer is complicated by the following EXCEPT : i) Mutations of BRCA1 and BRCA2 are heterogeneous ii) A small fraction of breast cancer is Mendelian iii) BRCA2 mutations exhibit incomplete penetrance iv) BRCA1 mutations exhibit incomplete penetrance v) Breast cancer primarily affects women H. The BCR-ABL translocation has which of the following properties? i) DNA repair deficiency ii) Loss of heterozygosity iii) Telomerase activation iv) Gain of function v) Chromosome instability I. You conduct a case-control association study between Type 1 diabetes and a certain haplotype at the MHC locus. The tallied frequencies are as follows: Patients Controls MHC A1 Locus 100 20 Without A1 Locus 60 120 What is the odds ratio of association between the autoimmune disease and the MHC haplotype? i) 4 ii) 6 iii) 8 iv) 10 v) 12 J. Massively parallel exome sequencing usually identifies 10–30 genes with deleterious mutations shared among sibs affected with a rare disease. Which of the following would NOT be helpful to identify the relevant gene? i) Eliminate common mutants by reference to the SNP database ii) Classify mutant changes as nonsense, frame-shift, deletion, conservative missense, synonymous, etc. iii) Study identical twins with the disorder iv) Perform linkage analyses on families v) Examine evolutionary conservation of the gene K. The following points concerning the Major Histocompatibility Complex (MHC) are correct EXCEPT : i) The class I and class II HLA molecules present antigens to B cells ii) GWAS analysis of the MHC would likely exhibit poor resolution due to large linkage disequilibrium blocks iii) The T cell receptor recognizes antigens in the context of HLA molecules iv) The HLA molecules show a relatively low level of variation due to selection against autoimmune disease v) The MHC is involved in the rejection of transplanted tissues

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4 L. Which of the following is NOT a likely explanation for why penetrance, severity, or age of onset of a Mendelian disease may vary in the population? i) Locus heterogeneity ii) Gene-by-environment interactions iii) Allelic heterogeneity iv) Linkage disequilibrium v) Triplet repeat expansion M. Germline missense mutations of p53 are often more deleterious than deletion mutations. The explanation is: i) p53 deletion mutation promotes apoptosis ii) p53 deletion mutations are removed during early development iii) Dominant-negative activity of mutant p53 iv) Gain-of-function in mutant p53 v) p53 deletion mutation promotes cell cycle arrest N. Shown below is a pathway for codeine metabolism. Two enzymes (CYP2D6 and CYP1A3) are involved, and each varies in the population in the level of activity. What is the genotype of an individual that requires the highest dose of codeine for relief of pain? i) Low CYP2D6, High CYP1A3 ii) Low CYP2D6, Low CYP1A3 iii) High CYP2D6, High CYP1A3 iv) High CYP2D6, Low CYP1A3 v) Insufficient data to determine Explanation: Low CYPD6 will reduce the amount of codeine converted to the active form (morphine), and high CYP1A3 activity will increase the rate of excretion, also reducing the amount of active drug. O. Which one of the following statements relating to pharmacogenetics is FALSE ? i) Drug dosage depends on the rates of absorption, metabolism, and excretion of the drug ii) Individuals in a population can respond differently to drugs depending upon genetic background iii) Some important considerations in drug development include efficacy, toxicity, and genetic interactions iv) Generally, drug development is done by screens that require an understanding of the protein targets v) Pharmacogenetic approaches can be applied to mendelian but not complex diseases Explanation: The only false statement is e, since pharmacogenetic approaches can be applied to treat any disease. An example of a complex disease treatment that has benefitted from pharmacogenetics is to define variants that influence statin adverse effects. P, Breast cancers expressing estrogen receptor are often treated with Tamoxifen, a competitive inhibitor of the estrogen receptor. A patient with high estrogen receptor levels in breast tumors showed no beneficial effect after Tamoxifen treatment. Which of the following do you suspect as contributing factor(s)? i) The patient has high CYP3A4 activity ii) The patient has low CYP2D6 activity iii) The patient has high HER2 levels on the surface of cancer cells Codeine CYP2D6 Excretion CYP1A3 Morphine

5 iv) The patient has both low CYP2D6 activity and high CYP3A4 activity v) The patient has both low CYP2D6 activity and high HER2 levels on the surface of cancer cells Explanation: When CYP2D6 activity is low, processing of Tamoxifen to the therapeutic molecule is reduced, explaining the lack of response to the therapy. The presence or absence of HER2 on the cancer cells does not influence response to Tamoxifen. Q. Suppose you are setting up a diagnostics laboratory. Which of the following genetic disorders would NOT be a good candidate for targeted mutation testing? i) Sickle cell anemia ii) Huntington disease iii) Fragile X syndrome iv) Cystic fibrosis v) Spinocerebellar ataxia R. Haplotypes for two SNPs (A and B) on chromosome 1 are in linkage equilibrium. The frequency of allele A1 is 0.4 and the frequency of allele B2 is 0.3. The frequency of haplotype A1,B2 is: i) 0.24 ii) 0.14 iii) 0.12 iv) 0.11 v) Cannot be determined from above (4pts) 2. Lupus is a common disorder that has a much higher incidence in women than in men due to a higher threshold for disease in men. Would sons of affected men or of affected women be more likely to develop lupus? Explain. Affected man probably have more risk genes than affected woman. Therefore, sons of affected men are at higher risk 45pts) 3. Sequencing of mitochondria from Native Americans has revealed a number of unrelated haplotypes. What does this suggest about the populating of the Americas? Multiple migrations (6pts) 4. List two reasons that mitochondrial DNA is particularly useful for examining the relationships of extinct hominids to present day human populations. • Mitochondria are haploid and the DNA does not recombine • There are multiple copies per cell and so sequencing is easier • Mitochondrial DNA replication is more error prone and, therefore, more variable than nuclear DNA in sequence

6 (15pts) 5. Shown below is a recessive disorder in which family members have been typed for SNP markers (1-10) with allele designations “1” and “2”. The boxed columns indicate the haplotypes of the individuals which include the disease gene locus. Note that there is consanguinity. (4pts) A. Indicate with an arrow which of the children’s haplotypes were inherited from the mother. +1 if correct, but not with arrow (4pts) B. Indicate with an “X” between markers where each recombination in the chromosome inherited from the mother has occurred. +2 for correct marks in addition to wrong marks (3pts) C. Indicate with an “X” at the bottom of the haplotype which of the mother’s chromosomes carries the disease allele. +1 if mark children’s chr as well (4pts) D. What is the most likely location of the gene? Indicate between which markers labeled 1- 10. 4-8 (+2 for each correct boundary) (5pts) 6. Tom’s aunt, on his mother’s side, is affected with a recessive hearing disorder. The prevalence of this condition in the population is 1/40,000. Tom’s wife, Melanie, is expecting a child. (2pts) A. Draw the pedigree (3pts) B. What is the probability that Tom and Melanie’s child has the recessive condition? q 2 = 1/40,00 q = 1/200 2/3 x 1/2 x 1/2 x q = (1/6)(1/200) = 1/1200 2 1 2 1 2 1 2 2 1 1 2 2 1 1 2 1 2 1 2 2 2 1 2 1 2 1 2 2 1 1 1 1 2 2 1 2 1 2 1 1 2 2 1 1 2 1 2 1 2 2 1 2 1 2 1 2 2 2 1 2 2 1 2 1 2 2 1 1 2 1 1 1 2 2 2 1 2 2 1 1 1- 2- 3- 4- 5- 6- 7- 8- 9- 10- 2 2 1 1 2 1 2 1 2 2 SNP 1 1 2 2 1 2 1 1 2 1 Tom -2 for no inclusion of q, but all else correct

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7 (10pts) 7. Shown below is a pedigree in which an X-linked recessive colorblindness (filled symbols) is segregating. The family members were typed for a microsatellite genetic marker on the X chromosome that exhibits two alleles (“A” and “B”), and the allele patterns are shown below the corresponding family members. (5pts) A. Assuming the disease gene resides on the X-chromosome, how many informative meiosis are there in the family? Four, since III-1 is not informative since the disease is recessive (5pts) B. Calculate a LOD score for linkage of the marker with the disease assuming recontinuation fraction = 20%. LOD = log10 (odds ratio) = lod = log 10 (0.8) (0.8) (0.2) (0.8) (0.5) (0.5) (0.5) (0.5) (5pts) 8. Arthritis shows high concordance in MZ twins (60%), moderate concordance in DZ twins (20%), but lower concordance in non-twin siblings (10%). (3pts) A. To determine the relative influence of genetics versus the environment as a cause of the trait, estimate the heritability of arthritis. H = 2 (MZ concordance 60% - DZ concordance 20%) = 2 (40%) = 80% (2pts) B. Why might the concordance of nontwin siblings be less than that of twin siblings? Twins share the environment to a greater extent (5pts) 9. A young woman in her 20s has a child with Down syndrome. What is a reason for her to undergo karyotype analysis? If she carries a chromosomal translocation, there is a large risk of Down syndrome in subsequent children I II III 1 2 1 2 1 2 3 4 5 allele A allele B

8 (5pts) 10. In his lecture on gene therapy, Don Kohn discussed treatment of severe combined immune deficiency (SCID) due to adenosine deaminase (ADA) deficiency. The disease can be treated by ex vivo modification of hematopoietic stem cells with lentivirus to provide the missing gene. Dr. Kohn indicated that post-treatment, the number and frequency of independent lentivirus insertion sites is monitored by high-throughput sequencing of white blood cell DNA. What is the reason for this? Explain. The insertions can activate oncogenes and the screen allows detection of clonal populations with enhanced growth, as would occur with oncogene activation (4pts) 11. Des Smith, our guest lecturer, indicated that schizophrenia, a common, severe disorder, often occurs in relatively young individuals (less than 30 years of age). Since the disease has a large effect on reproductive fitness, propose an explanation for the fact that it is relatively common in the population. It could be due to balanced selection (10pts) 12. After sequencing 50 liver tumors, you find missense and termination mutations in protein A, as shown below. (3 pts ) A. If Protein A mutations act as driver mutations in the liver tumors, is it more likely that Protein A acts as an oncogene or a tumor suppressor? (1 point) Explain your reasoning (2 points). The mutation pattern suggests tumor suppressor because there are mutations throughout the length of the protein, and abundant premature stop codons, which would cause loss of protein function. In contrast, oncogenes are pathogenic when they acquire gain-of-function mutations. (3 pts ) B. In addition to sequencing liver tumors, you are also utilizing a transformation assay in 3T3 cells to isolate tumorigenic genes from liver tumors. Are you likely to isolate the gene for Protein A using this assay? Explain your answer. No; the transformation assay identifies dominant mutations that induce cell transformation. Tumorigenic mutations in Protein A are loss-of-function mutations and these will not be evident because 3T3 cells will express wild-type Protein A. (4 pts ) C. 20–30 years after the initial diagnosis of liver cancer, some individuals with mutations shown above developed bone cancer. The bone tumors all show mutations in protein A, but otherwise do not share mutations with the original liver cancers, suggesting that the bone tumors are NOT due to metastasis from the liver. Offer an explanation for the high rate of bone tumors in this set of liver cancer patients. Suggests that a Protein A mutation in these individuals are present in the germline and can undergo LOH during the lifetime in different tissues.

9 (5pts) 13. In this figure from Parma et al., what would it mean if the Rspondin-1 expression appeared to be equal in males and females? Rspondin-1 likely does not regulate sex differentiation Full credit: Not causing sex reversal +3 if say they would be all female (10pts) 14. You are a graduate student, and your lab is trying to utilize a novel ABE (adenine base editor) to edit the pathogenic allele ( HBB^S) of the HBB gene to a non-pathogenic variant ( HBB^G) in HSPCs for transplantation into immunodeficient mice. (5pts) A. A collaborator asks you how much of the wildtype HBB protein (β^W - globin ) you would expect to be produced after editing 20% of the HBB^S allele. What is your response and why? No wildtype B-globin protein should be produced, as ABE is being used to generate a benign variant of HBB allele distinct from wildtype. (5pts) B. After a power outage, some of your isolated bone marrow cells from mice transplanted with ABE-edited HSPCs died in the non-functional incubator. There are not enough edited bone marrow cells to perform a secondary transplant on 6 mice; you can only transplant 3 mice with 90:10 edited:unedited bone marrow, 4 mice with 75:35 edited:unedited bone marrow, 5 mice with 50:50 edited:unedited bone marrow, or all six with 20:80 edited:unedited. However, you recall a key experiment in investigating base-editing requirements haematological correction. Based on the Newby et al. results below, which ratio(s) will allow maintenance of at least 70% of the B^G - globin protein 16 weeks post-transplantation? Explain your answer. 90:10 and 75:35 would both work. Panel C shows a ratio of 60:40 edited:unedited is enough to maintain an HBB^G allele frequency above 20%. Panel D shows the 20% allele frequency maintains 70% of the B-globin pool as the benign B^G protein. (5pts) 15. According to this figure in Tishkoff et al. on haplotype decay which west African country has had the derived haplotype for the longest time? Tanzania

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10 (6pts) 16. Shown below is RNA expression of KDM6A in (B)CD4+ T cells from spleen and (C) CD4+ T cells from lymph nodes in mice. What is the significance of studying XX/XY mice as well as the male/female mice? The authors are able to determine whether hormones from sex organs, sex-specific gene dosage, or both, contribute to the increased expression of Kdm6a in females. (15pts) 17. Below is a regional Manhattan plot from the Wu et al. paper. The purple diamonds denote the tag SNPs. (5pts) A. What is the difference between the dots colored green compared to red? Red dots represent SNPs that are more highly correlated with the tag SNPs identified by GWAS than the SNPs shown as green dots. OR Green dots represent SNPs that are less correlated with the tag SNPs identified by GWAS than the SNPs shown as red dots. (5pts) B. SNP rs7206735 in located in a non-coding, non-regulatory intronic region of a gene. What could explain its identification by GWAS as being significantly associated with esophageal squamous cell carcinoma (ESCC) risk? Incorporate data shown in the plot in your answer. The SNP could be in LD with rs4785204. The locus shows a minimal/low recombination rate. (5pts) C. Why can we not conclude that rs4785204 and/or rs7206735 are causal mutations of ESCC? GWAS identifies whether a SNP appears with a disease in a statistically significant way, but it does not offer functional links between a mutation and disease.

11 (10pts) 18. In the pedigree below, the female in generation I developed early onset breast cancer Her four children were tested for BRCA1 variants by sequencing the entire gene. Variants at two positions (nucleotide 60 and 70) were detected, with the genotypes shown. Using information from the paper by Findlay et al. (Week 8) shown below the pedigree, which individuals in generation III would you recommend undergo BRCA1 sequencing because of increased risk for inheriting deleterious variant(s)? Explain your answer. Individuals 1, 2, 5 and 6 are potentially at risk for carrying a deleterious BRCA1 allele. The data show that the A and C alleles at position 60 are both functional. However, at position 70, the T allele is functional but the A allele is non-functional. Therefore, individuals with the A genotype at position 70 can pass a non-functional allele to their offspring (1, 2, 5, 6). (6pts) 19. Below shows data from Findlay et al. on Saturation Genome Editing from Week 8. (3pts) A. Of the 3 identified variants, which variant(s) is most likely to downregulate BRCA1 transcription compared to wildtype? Explain. II, it has a low RNA score while I and II have scores of 0. (3pts) B. You are told one of the three shown variants leads to an amino acid substitution of Alanine in place of a Histidine at a catalytic site. Which is most likely and why? I, because it is annotated as pathogenic with a low function score, but the mutation does not affect the mRNA levels (RNA score 0).

12 (5pts) 20. What is a likely explanation for the fact that ultra-rare variants are rare? Ultra-rare variants are selected against because they have larger effect size. (+5, all or nothing) (6pts) 21. GWAS studies have identified genetic variants that are associated with complex traits and diseases. Combining the genotypes of several variants to generate Polygenic Risk Scores (as was done in Week 10 paper by Turley et al.) is an approach to predict likelihood of specific traits. Describe 3 factors that influence the accuracy of Polygenic Risk Score predictions. • Ancestral/ethnic background—Ideally, should be the same as the population in which the GWAS was performed to identify risk variants. • Pleiotropic effects of genetic variants on multiple traits. • Effects due to environmental and genetic factors not accounted for in the risk score. • Lack of genetic variation within a family compared to between families. • Many common traits and diseases are not binary, but rather on a continuum. (5pts) 22. How does Singh et al’s GRIN2A findings in figure 3b support the theory of hypofunction of glutamatergic signaling through NMDA receptors as a possible mechanism of schizophrenia pathogenesis? • GRIN2A is a NMDA receptor subunit (+1 points) • GRIN2A is predominantly expressed during late childhood and adolescence (+2 points) • Temporal expression of GRIN2A matches the observed epidemiological schizophrenia age of onset (+2 points). (5pts) 23. EXTRA CREDIT – Please rank the three papers that you consider the best (B) and the three that you consider the least (L) helpful in terms of teaching human genetics. ____ Choi et al. (2009) Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. ____ Tishkoff et al. (2007) Convergent adaptation of human lactase persistence in Africa and Europe. ____ Franke et al. (2016) Formation of new chromatin domains determines pathogenicity of genomic duplications. ____ Wu et al. (2012) Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions. ____ Parma et al. (2006) R-spondin1 is essential in sex determination, skin differentiation and malignancy. ____ Findlay et al. (2018) Accurate classification of BRCA1 variants with saturation genome editing. ____ Newby et al. (2021) Base editing of haematopoietic stem cells rescues sickle cell disease in mice. ____ Singh et al (2022) Rare coding variants in ten genes confer substantial risk for schizophrenia. ____ Itoh et al. (2019) The X-linked histone demethylase Kdm6a in CD4 + T lymphocytes modulates autoimmunity ____ Turley et al. (2021) Problems with using polygenic scores to select embryos. END OF EXAM! HAVE A GREAT SPRING BREAK! +2 each

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CM156-Final-Winter 2023-Mar. 24-KEY

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