CM156-Final-Winter 2019-KEY

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CM156

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1 Name (Last) (First) Student ID KEY CM156/256 Final Exam (March 18, 2019) BEFORE YOU BEGIN THE EXAM, circle your discussion teaching assistant: GREGORY MARIA SAMUEL 1. (75pts) 7. (10pts) 13. (5pts) 2. (5pts) 8. (10pts) 14. (10pts) 3. (10pts) 9. (5pts) 15. (10pts) 4. (5pts) 10. (5pts) 16. (10pts) 5. (5pts) 11. (10pts) 17. (5pts) 6. (5pts) 12. (10pts) 18. (5pts) 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 (75 pts, 1. Indicate the best answer for each of the following multiple-choice questions 3pts each) A. A female mouse has inherited a paternal X chromosome carrying a Duchenne Muscular Dystrophy (DMD) gene mutation as well as a null mutation for the XIST gene (introduced by gene targeting). She is mated to a normal male. The percentage of male pups exhibiting DMD will be about: i) 0 ii) 25% iii) 50% iv) 66% v) 100% B. In Vollrath et al (Week 2 paper, Y chromosome), the authors were unable to examine the pseudoautosomal (PAR) regions of the Y chromosome. The reason for this is that: i) The Y chromosome lacks PARs ii) The PAR region is highly polymorphic iii) The STSs on the PAR region were eliminated by the authors screen iv) PARs are required for normal chromosome pairing v) STSs in the PAR region are highly repetitive due to numerous gene duplications C. The following is true of “linkage disequilibrium” EXCEPT : i) It is a function of both the number of meiotic events and genetic distance ii) It can be assessed from unrelated individuals iii) It can be affected by selection iv) It is measurable on the scale of kilobases v) It generally involves duplications D. The following is true of “linkage” EXCEPT : i) Can be seen with inheritance from parent to offspring ii) Can be measured on a scale of recombination units iii) Can be detected only in meioses of heterozygous individuals iv) Can be measured with unrelated people v) Can be seen with extended families E. In the pedigree shown below, what is the % of DNA shared (IBD) by III-1 and III-2? i) 1/8 ii) 1/12 iii) 1/16 iv) 1/24 v) 1/32 F. In the above pedigree, what is the approximate chance IV-1 will be affected for the rare recessive Gaucher disorder that affects II-2? i) 1/100 ii) 1/50 iii) 1/35 iv) 1/20 v) 1/10 IV-1 III-2 III-1 II-3 II-2 II-1 I-3 I-2 I-1

3 G. Massively parallel exome sequencing usually identifies 10–30 candidate mutant genes 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) Compare gene location with linkage data v) All are useful H. Which of the following observations would NOT support the “Out of Africa” hypothesis of origin of modern humans? i) African populations are at the root of the phylogenetic tree among the world’s populations ii) Native American populations have a higher level of genetic diversity than Africans iii) Modern human populations share the majority of common genetic variants iv) Some populations but not others show admixture with Neanderthal DNA v) The mitochondrial Eve lived at the same time as the Y chromosome Adam I. In 1918, R.A. Fisher proposed a model to explain continuously inherited (quantitative) traits such as height and blood pressure. His model: i) Assumes that the traits are determined by a combination of many Mendelian factors ii) Postulated epistatic interaction iii) Assumes that environment plays an important role iv) Heritability is about 50% v) None of the above J. The Huntington Disease (HD) gene was originally mapped by linkage to a chromosome marker D4S10. It is about 2 centiMorgans from the disease gene. In the family segregating for HD below, the alleles of D4S10 are indicated by “1” or “2”. What is the chance that the 3d generation individual will NOT be affected? i) 0% chance ii) 2% chance iii) 4% chance iv) 98% chance v) 100% chance K. Fragile X syndrome and Huntington Disease exhibit the following features characteristic of most Mendelian diseases EXCEPT : i) Segregate in families as single genes ii) Due to a sequence change in a gene iii) High penetrance iv) Relatively small environmental influence v) Stable genotype from generation to generation 1,1 2,2 1,2 1,2 1,2 2,2 2,2 ?

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4 L. A family has a child with developmental delay, and imprinting is suspected. The clinic orders DNA testing of two SNPs in the suspected region What is the likely cause of the disorder based on the genotypes: i) Trisomy ii) Maternal uniparental disomy iii) Paternal uniparental disomy iv) Chromosomal deletion of imprinted region v) None of the above M. Which of the following assumptions is required for GWAS? i) The population of interest is in Hardy-Weinburg equilibrium ii) The condition being studied exhibits non-Mendelian inheritance iii) At least one marker is (or is in LD with) the causal variant iv) The variance in the condition due to genetics must be greater than the variance due to environment v) All of the above N. In Alzheimer's disease, both the APOE4+ allele and hypertension increase the risk of developing the disease. A recent study suggested the APOE4+ allele was a larger risk factor among hypertensive individuals than among non-hypertensive individuals. This is an example of: ( note—i or iv were each accepted as correct answers ) i) Gene-environment interaction ii) Pleiotropy iii) Incomplete penetrance iv) Epistasis v) Allelic heterogeneity O. You study a group of patients (N=200) with arthritis and a group of controls (N=200). You type all of the individuals for an allele of a class II HLA gene that has previously been associated with the disease with the following results: What is the odds ratio for the HLA allele? i) 2 ii) 4/3 iii) 8/3 iv) 6 v) None of the above P. Which of the following capabilities would a cell acquire in the event that telomerase is improperly turned on? i) Self-sufficiency in growth signals ii) Insensitivity to anti-growth signals iii) Apoptosis avoidance iv) Limitless replicative potential v) Tissue invasion SNP1: A,G A,G AA A,G SNP2: G,G C,C G,C C,C Susceptible allele Patients Controls Carriers 80 40 Non-carriers 120 160

5 Q. Genetic counseling for breast cancer is complicated because: i) Mutations of BRCA1 and BRCA2 are heterogeneous ii) Less than 15% of breast cancer is Mendelian iii) BRCA2 mutations exhibit incomplete penetrance iv) BRCA1 mutations exhibit incomplete penetrance v) All of the above R. Differences between XX and XY cells include all of the following EXCEPT : i) Expression levels of some pseudoautosomal genes ii) Expression levels of some X chromosome genes iii) Heterochromatin iv) Imprinted genes v) Repetitive sequences S. All of the following are likely to contribute to a cancer EXCEPT : i) Activation of telomerase expression ii) Translocation resulting in BCR-ABL chimeric protein iii) Nonsense mutations of mismatch repair enzyme iv) Loss of heterozygosity in region containing the HER2 gene v) Missense mutation of P53 T. Polymorphisms in cytochrome P450 genes influence individual drug responses. Which of the following genotypes might result in inefficient pain reduction by a standard dose of codeine? i) CYP2D6 gene duplication ii) CYP2D6 null mutation in one allele iii) CYP3A4 null mutation in one allele iv) Foods rich in Vitamin K v) CYP3A4 gene duplication and foods rich in Vitamin K U. Fibroblast cells from familial hypercholesterolemia (FH) patients have much higher levels of HMG-CoA reductase, the rate limiting enzyme in cholesterol synthesis, than fibroblasts from normal subjects. The explanation for this is: i) FH individuals exhibit defective feedback regulation of HMG-CoA reductase ii) FH individuals accumulate high levels of plasma cholesterol and this is toxic to cells iii) Low Density Lipoproteins are taken up poorly by FH cells iv) The LDL receptor acts as a transcriptional activator of HMG-CoA reductase v) The HMG-CoA reductase receptor gene undergoes amplification in FH V. Precision medicine is a relatively recent approach that seeks to integrate genetic, environmental, and other health-related data to diagnose and treat patients on a personalized level. Which of the following has been the MOST important in facilitating this new strategy? i) Development of new bioinformatics tools ii) New studies involving gene-environment interactions iii) Increase in genetic counseling program spots iv) Better understanding of drug responses based on genomic profiles v) Drastic reduction in cost of genome sequencing

6 W. Which of the following would be evidence that a disease is at least partially caused by de novo germline mutations? i) Affected individuals exhibit mutations at the same genomic loci ii) Monozygotic twins are more likely to both develop the disease than fraternal twins are iii) Older individuals are more likely to develop the disease iv) Risk of developing the disease is positively correlated with paternal age v) All of the above X. Saturation Genome Editing (SGE) would be MOST useful for studying which of the following? i) Cystic Fibrosis ii) Huntington’s disease iii) CAD iv) Type 2 Diabetes v) ESCC Y. The following points concerning the Major Histocompatibility Complex (MHC) are correct EXCEPT : i) The class I and class II HLA molecules present antigens to T 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 independently of 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 (5pts) 2. The pedigree shown below shows an imprinted disorder. What is the chance that the child IV-3 will be affected? Explain. Paternally imprinted, 25% chance that IV-3 will be affected. I II III I 4 2 3 1 2 1 3 5 4 2 1 1 2 7 6 3

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7 (10pts) 3. You type a series of microsatellite markers (with up to 8 alleles each, indicated by numbers 1- 8) in the family below. IA IB IIA IIB (2pts) A. 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 grandfather’s haplotype) (2pts) B. Circle the informative meiotic products. (2pts) D. Which region of the genome (between which A-G markers) most likely contains the disease gene? C-G (4pts) E. Calculate the lod score for linkage of marker E with the disease gene at a recombination fraction ( θ ) of 0.3 (just set up the equation). log 10 (0.7) 4 (0.3) 0 (0.5) 4 (5pts) 4. Cystic fibrosis is a recessive disease and more than 70% of cases are due to a 3 nucleotide deletion encoding a phenylalanine residue at amino acid position 508 (denoted ∆ F508) in the CFTR gene. Indicate which strategies could be used to generate a mouse model to study the effects of this mutation (select all vectors that apply by checking the line at the left). 3 4 2 2 3 5 7 2 5 5 3 7 2 6 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 4 5 3 6 7 5 6 2 5 5 3 7 2 6 3 4 2 2 3 5 6 3 4 2 2 3 5 7 3 4 2 3 7 2 6 4 5 3 6 7 5 6 3 4 2 2 3 5 7 3 4 2 2 3 5 7 A B C D E F G markers IIIA IIIB IIIC IIID IIIE IIIF

8 (10pts) 5. John’s wife, Mary, has a first-degree cousin who has heterozygous familial hypercholesterolemia. Both Mary and John have normal cholesterol levels. John and Mary have a child, Lisa. Draw the pedigree and calculate the probability that Lisa has homozygous FH, given that the frequency of heterozygous FH is 1/500 (just set up the equation). Zero probability. Full credit was given for this problem if your pedigree was drawn correctly. (10pts) 6. Suppose you type two SNP markers (“A” and “B”) 20kb apart in Nigerian and Icelandic populations. The frequencies of the polymorphism and their haplotypes are shown. (5pts) A. Are the two SNPs in linkage disequilibrium in the populations? Explain. Nigerian population—not in LD Icelandic population—exhibits LD (frequency of haplotypes not predicted by genotype frequencies) (5pts) B. Propose an explanation for any differences between the population. Founder effect of bottleneck in Icelandic population (10pts) 7. The following questions refer to the figure below. The arrow shows the position of a candidate SNP for a disease association. Genes are shown at the top, and peaks for histone marks characteristic of active enhancers are shown on the tracks at the bottom. (3pts) A. How might one determine which gene(s) are affected by the enhancer region containing the peak? Test for interaction of the peak region with the genes/promoters in the region using techniques such as chromatin conformation capture (3pts) B. How might you test for the effect of the SNP on enhancer function? Clone the peak region containing the SNP for each allele and insert upstream of a reporter gene to assess the ability of each allele to increase reporter gene expression. (4pts) C. Is it likely that the enhancer peak containing the SNP acts in all tissues? Explain. It is not likely to act in some tissues since the active histone mark is not evident in T cells. Nigerian population Icelandic population SNPA, allele A 1 0.6 SNPA, allele A 1 0.7 SNPA, allele A 2 0.4 SNPA, allele A 2 0.3 SNPB, allele B 1 0.7 SNPB, allele B 1 0.7 SNPB, allele B 2 0.3 SNPB, allele B 2 0.3 Haplotype A 1 B 1 0.42 Haplotype A 1 B 1 0.62 Haplotype A 1 B 2 0.18 Haplotype A 1 B 2 0.08 Haplotype A 2 B 1 0.28 Haplotype A 2 B 1 0.08 Haplotype A 2 B 2 0.12 Haplotype A 2 B 2 0.22 Liver T cell Macrophage SNP

9 (10pts) 8. Describe what experiment/study would be used to address the following questions: (2pts) A. Whether an amino acid is critical to a protein’s function? Ortholog paralog seq. comparison (2pts) B. Whether a mutation was inherited or is de novo in an individual? Sequence triad (mom dad patient) (2pts) C. Whether genes on the X or Y chromosomes are responsible for sex differences in a trait such as body weight? Four core genotypes mouse model (2pts) D. Identification of the mutation underlying a disease exhibiting Mendelian inheritance (in a particular individual)? Whole exome sequencing (2pts) E. Common variants that contribute to an individual’s risk for developing Alzheimer’s or schizophrenia? GWAS (5pts) 9. In her lecture on genetic counseling, Judy Fan mentioned several challenges that counselors may face and provided some case studies to demonstrate. Briefly discuss one of these challenges below. 1. Case 1 – phenotype difficult to distinguish (TTR amyloidosis = rare, with variable expression and penetrance, can result in many different phenotypes which makes ordering relevant tests difficult) 2. Case 2 – Variants of unknown significance in HTAD provide challenge in interpretation – sometimes, not enough is known about the disorder even if the right test is ordered 3. Case 3 – ethical challenge (do no harm); if patient tests positive for a genetic disorder but neglects to inform relatives who are at risk, counselor needs to weigh this risk of others dying when they could have done something against the need for patient confidentiality. (5pts) 10. To prevent blood clots, a patient was prescribed Warfarin based on his weight. A month later, he was admitted to the hospital for bleeding due to excessive Warfarin action. He was subsequently shown to have two CYP2C9*3 alleles, which have reduced activity. Offer an explanation for the bleeding in response to Warfarin. CYP2C9 metabolizes Warfarin. Lower CYP2C9 activity leads to longer Warfarin half-life and higher activity, which was not taken into account when the dose was determined strictly based on weight.

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10 (5pts) 11. Vollrath et al (Week 2, Y chromosome map) used STS markers to map the Y chromosome. Using the same logic discussed in the paper, draw the Y chromosome showing the order of the STSs in the above table. (10pts) 12. From Rossidis et al. (Week 4 paper, in utero CRISPR-mediated….) (3pts) A. List 3 types of mutations that are not possible given the capabilities of base editor 3 genome editing. Insertion, deletion, translocation (4pts) B. What can you conclude regarding the significant difference in percent edited alleles of Hpd at the 3 month time point? Survival advantage conferred, subsequent expansion of cells (3pts) C. If instead the results of the BE3- Hpd experiment had been the figure below, what would you conclude regarding the significant drop in edited alleles from DOL1 to 3 months? Edits were not stable, cells died resulting in the drop from DOL1 levels to 3 month levels STS1 STS2 STS3 STS4 STS5 STS6 Sample 1 + + - - - - Sample 2 - + + + + + Sample 3 - - - - + + Sample 4 - - - - - + Sample 5 + + - + - - 6 5 3 4 2 1

11 (5pts) 13. Shown on the right is Fig. 3a/b from Tishkoff et al. (Week 6, Lactase persistence). Give two possible reasons why individuals homozygous for the ancestral allele sometimes still exhibit lactase persistence. - LP is complex trait - Alternative causal variants - False positives (LTT field test results may be rough/not as well-controlled) (5pts) 14. From Findlay et al. (Week 7, Accurate classification of BRCA1…). If a variant is classified as ‘non-functional’ in the saturation genome editing analysis and also observed at an allele frequency of 2% in a certain population from the gnomAD database, what would you conclude regarding the pathogenic mutation’s prevalence? (Note: false positive is not the correct answer) Incomplete penetrance, which explains why seemingly healthy people have the variant at a common allele frequency (10pts) 15. In the paper by Wu et. al., (Week 8), SNP rs6503659 was identified to be associated with esophageal squamous cell carcinoma (ESCC). The authors point out two genes in the region marked by this SNP, JUP and HAP1 . JUP encodes gamma-catenin which, if its expression is altered, has a potential role in cancer, but the gene product of HAP1 does not have a clear role in cancer. (3pts) A. In designing association studies, it is important to consider confounding factors that may lead to spurious associations. List 3 factors that need to be considered in developing a GWAS model. Multiple possible answers: population substructure, sex as a covariate, age as a covariate, gene-environment interactions (4pts) B. Why do the authors choose to highlight these two genes in particular? Are you convinced that either HAP1 and JUP are causal for the disorder? Explain. They are the genes closest to the index SNP rs6503659. No, there are many other genes nearby the region marked by this SNP and a long-range interaction could also be taking place. (3pts) C. Global gene expression in esophagus has been performed for hundreds of individuals and is publically available. How could this help in identifying the causal gene? Can assess if peak SNP affects expression of the candidate genes

12 (10pts) 16. Sampson et al. (Week 9, Gut microbiota) studied the effect of gut microbes in a mouse model of Parkinson’s Disease (PD). (6pts) A. Based on the mechanism proposed by Sampson et al., what would be the effect of treating the following mice with SCFAs in regards to PD symptoms? (Circle one) (i) SPF-WT Increase Decrease No Change (ii) GF-ASO Increase Decrease No Change (iii) SPF-ASO w/ Abx Increase Decrease No Change (iv) GF-ASO w/ Abx Increase Decrease No Change (v) Ex-GF-ASO Increase Decrease No Change (4pts) B. Shown on the right is Figure 6A from Sampson et al. What were the authors trying to show with these data? Shows that recipient mice clustered together based on shared human donors AND that healthy and diseased donors gave rise to different microbiota compositions. (5pts) 17. From Li et al. Week 10, answer the following question regarding alternative results for Figure 4A. What would you conclude regarding the performance of the genome model, and more specifically their use of rare SNVs in the model, had the results been the figure below? The genome model has same ability to identify true negatives as the genome + EHR model but performs worse in terms of identifying true positives. I would conclude that the contribution of rare SNVs to AAA risk is much lower than originally believed, and incorporation of common variants maybe improve performance.

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13 (5pts) 18. Please rank the two papers that you consider the best (B) and the two that you consider the worst (W). ____ 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. ____ Vollrath et al. (1992) The human Y chromosome: a 43-interval map based on naturally occurring deletions. ____. Findlay et al. (2018) Accurate classification of BRCA1 variants with saturation genome editing. ____ Parma et al. (2006) R-spondin1 is essential in sex determination, skin differentiation and malignancy. ____ Wu et al. (2012) Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions. ____ Rossidis et al. (2018) In utero CRISPR- mediated therapeutic editing of metabolic genes. ____Sampson et al. (2016) Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease. ____ Chen et al. (2016) Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing. ____ Li et al. (2018) Decoding the genomics of abdominal aortic aneurysm. END OF EXAM! HAVE A GREAT SPRING BREAK!

CM156-Final-Winter 2019-KEY

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