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NAME: __________________________________________________________ GRADE: _______________________ / 125 SECTION 1: _________ / 10 SECTION 2: _________ / 11 SECTION 3: _________ / 10 SECTION 4: _________ / 24 SECTION 5: _________ / 21 SECTION 6: _________ / 49 BIOS E-­‐145 (GENETICS OF HUMAN DISEASE) MIDTERM EXAM MARCH 25, 2013 RULES FOR THE MIDTERM EXAM: 1. SIT EVERY OTHER SEAT. 2. WRITE IN PEN ONLY. ANSWERS IN PENCIL WILL NOT BE GRADED. 3. NO TALKING ONCE EXAMS ARE HANDED OUT. 4. PUT AWAY EVERYTHING OTHER THAN YOUR CALCULATOR AND YOUR PENS. 5. YOU MAY NOT LEAVE DURING THE LAST 15 MINUTES OF THE EXAM. PLEASE STAY SEATED AFTER 9:25PM. 6. READ EACH QUESTION CAREFULLY. 7. ANSWER EVERY QUESTION. 8. USE ONLY THE SPACE PROVIDED FOR SHORT ANSWERS. 9. PLEASE WRITE LEGIBLY – IF I CAN’T READ IT, I CAN’T GRADE IT! GOOD LUCK! Page 1 of 17 NAME: __________________________________________________________ PROBABILITY AND STATISTICS FORMULAS Page 2 of 17 NAME: __________________________________________________________ SECTION 1: TRUE OR FALSE (10 POINTS) SECTION 1 GRADE: _______________ / 10 For questions 1-­‐5, answer whether the following statements are true or false. If false, explain why, in no more than ONE SENTENCE. (2 POINTS EACH) 1. If you test 1000 different SNPs and find that one of them is associated with a particular trait with a p-­‐value of 0.043, that means that SNP is definitely associated with the trait. 2. Mendel’s Principle of Independent Assortment (which holds that the inheritance of one trait does not affect the inheritance of another trait) means that the genes for the two traits are either on different chromosomes or far apart on the same chromosome. 3. When looking for modifiers of Mendelian traits, you should always be able to find genetic modifiers – there’s no need to look for evidence that genetic modifiers exist before doing further studies. 4. Creutzfeldt-­‐Jacob disease (CJD) and familial fatal insomnia (FFI) are both caused by dominant mutations in the same gene. In both cases, there is the same mutation at codon 128, but individuals with CJD have a certain polymorphism at codon 129 of the same allele and individuals with FFI have a different polymorphism at codon 129. This is an example of a trans effect altering disease phenotype. 5. The variable severity of cystic fibrosis due to different mutations in the CFTR gene is an example of allelic heterogeneity. Page 3 of 17 NAME: __________________________________________________________ SECTION 2: FILL IN THE TABLE (11 POINTS) SECTION 2 GRADE: _______________ / 11 (0.5pts each) For each disease, fill in the table with the relevant gene and the mode of inheritance. Gene options: beta globin, BRCA1, BRCA2, CFTR, FGFR3, glucocerebrosidase, HFE, huntingtin, multiple genes, PAH, NF1 Mode of inheritance options: autosomal dominant, autosomal recessive, X-­‐linked dominant, multiple contributing genes, multiple modes of inheritance. Note: do not consider inheritance of modifier genes for this table. 6. Table of diseases Disease Relevant gene(s) Mode of inheritance Achondroplasia Age-­‐related macular degeneration Cystic fibrosis Gaucher disease Hemochromatosis Huntington’s disease Hypogonadotropic hypogonadism/Kallmann syndrome Mendelian breast cancer syndromes Neurofibromatosis type I Phenylketonuria Sickle cell disease Page 4 of 17 NAME: __________________________________________________________ SECTION 3: PEDIGREE INHERITANCE PATTERNS: DETERMINE THE MODE OF INHERITANCE SECTION 3 GRADE: _______________ / 10 For each of the pedigrees in questions 7 to 11, name the MOST LIKELY mode of inheritance. For all questions, assume the trait is RARE and has COMPLETE PENETRANCE. (2 POINTS EACH) 7. Pedigree 1: ________________________________________________ 8. Pedigree 2: _________________________________________________ 9. Pedigree 3: ________________________________________________ Page 5 of 17 NAME: __________________________________________________________ 10. Pedigree 4: ________________________________________________ 11. Pedigree 5: ________________________________________________ Page 6 of 17 NAME: __________________________________________________________ SECTION 4: PROBABILITY, STATISTICS, AND CALCULATIONS SECTION 4 GRADE: _______________ / 24 For questions 12 to 16, answer each question in the space provided. You must show your work for full credit. 12. An individual with genotype Aa BB Cc Dd EE is crossed with an individual with genotype aa bb cc dd ee. Assuming all loci undergo independent assortment, what fraction of the progeny are expected to have genotype Aa Bb cc dd Ee? (2 POINTS) 13. In Drosophila, the dominant allele Cy results in curly wings (wildtype wings are straight), but homozygous Cy/Cy is lethal (the embryos do not survive). On another unlinked gene, B, a dominant mutation B results in brown eyes rather than the wildtype red eyes. In a cross of Cy/+ B/+ × Cy/+ B/+, where the + sign denotes the wildtype alleles of both genes, what is the expected ratio of curly-­‐wing, red-­‐eyed: straight-­‐wing, brown-­‐eyed flies? (4 POINTS) 14. This pedigree is for an autosomal recessive trait with a penetrance of 75%. The bands in the gel are restriction fragments used to identify the wild-­‐
type allele A (longer band) and the mutant allele a (shorter band). Using all of the information in the pedigree, what is the probability that the fetus III-­‐1 will be unaffected? Show all of your work. (5 POINTS) Page 7 of 17 NAME: __________________________________________________________ 15. This pedigree is for a rare autosomal recessive trait with complete penetrance. What is the probability that at least one of IV-­‐1, IV-­‐2, and IV-­‐4 is a carrier? (5 POINTS) 16. This pedigree is for an extremely rare autosomal recessive trait with complete penetrance. (8 POINTS TOTAL) a. Using only the information in generations I and II, what is the probability that individual II-­‐2 is a heterozygous carrier? (2 POINTS) b. Ignoring the sibship in generation IV, what is the probability that individual III-­‐1 is a heterozygous carrier? (2 POINTS) c. Ignoring the sibship in generation IV, what is the probability that individuals III-­‐1 and III-­‐2 are both heterozygous carriers? (2 POINTS) d. Does the sipship in generation IV increase, decrease, or not affect the probability that individuals III-­‐1 and III-­‐2 are both heterozygous carriers? (2 POINTS) Page 8 of 17 NAME: __________________________________________________________ SECTION 5: SHORT ANSWER SECTION 5 GRADE: ________________ / 21 For questions 17 to 21, briefly answer each question in the space provided. 17. Mendel’s Principle of Segregation requires a number of assumptions. Name three of them. (3 POINTS) 18. Name and briefly describe two approaches (one sentence or less per approach) that can be used to identify genes that cause Mendelian diseases. (3 POINTS) 19. Explain in three sentences or less (bullet points are fine!) how you identify linkage between two genes or between a gene and a molecular marker. (4 POINTS) Page 9 of 17 NAME: __________________________________________________________ 20. Name and briefly define/explain three different sources of phenotypic heterogeneity in the expression of a disease. NO MORE THAN ONE SENTENCE PER SOURCE, BULLET POINTS OK. (6 POINTS) 21. Discuss in no more than three sentences some of the considerations necessary when designing a study to search for modifiers of Mendelian diseases. Bullet points ok. (5 POINTS) Page 10 of 17 NAME: __________________________________________________________ SECTION 6: DATA ANALYSIS SECTION 6 GRADE: ________________ / 49 For questions 22 to 28, briefly answer each question in the space provided. 22. This figure is from Linus Pauling’s 1949 paper identifying the molecular basis of sickle cell disease. The experiment performed to generate the data here looked at the mobility of different types of hemoglobin molecules from normal individuals, individuals with sickle cell anemia, and individuals with sickle cell trait (heterozygotes). The arrow in each part of the figure gives a basis for comparison (you can think of it like an axis on a graph). PLEASE ANSWER EACH PART OF THE QUESTION IN ONE SENTENCE. (6 POINTS TOTAL) a. From this figure, what do you conclude about the mobility of normal vs. sickle cell hemoglobin? (2 POINTS) b. From this figure, what do you observe regarding the hemoglobin from individuals with sickle cell trait? (2 POINTS) c. Compare the mobility profile of hemoglobin from individuals with sickle cell trait and the 50-­‐50 mixture of normal and sickle cell hemoglobin. (2 POINTS) Page 11 of 17 NAME: __________________________________________________________ 23. This figure is from the 1996 paper by Feder et al mapping the HFE gene to hereditary hemochromatosis. The authors genotyped 45 markers in 101 patients with hereditary hemochromatosis (HH) and 64 controls. They calculated Pexcess, which is a measure of linkage disequilibrium, at each marker. This figure (part a) shows the map of Pexcess against the physical location for each marker. In part b of this figure, the deviation from Hardy-­‐Weinberg equilibrium is mapped. (9 POINTS TOTAL) a. In one sentence, what was the goal of this figure? (2 POINTS) b. In part a, the authors calculated Pexcess, a measure of linkage disequilibrium. In part b, the authors calculated F, the proportionate excess of homozygotes, which is greatest at the disease locus. In one sentence, how do the regions identified by the two approaches compare? (2 POINTS) c. What do these two approaches tell us about the location of the HH gene? Do they define precise boundaries? How might you narrow down the region further? NO MORE THAN 4 SENTENCES – BULLET POINTS OK. (5 POINTS) Page 12 of 17 NAME: __________________________________________________________ 24. This table is from the 1989 paper by Kerem et al identifying the gene for cystic fibrosis. It looks at the distribution of CF and non-­‐
CF chromosomes with and without the 3-­‐bp ΔF508 deletion. They also compared CF with pancreatic insufficiency (CF-­‐PI) and CF with pancreatic sufficiency (CF-­‐PS). (8 POINTS TOTAL) a. In one sentence, what was the goal of this figure? (2 POINTS) b. In no more than two sentences, describe the main findings of this figure. How often is the ΔF508 mutation seen in CF chromosomes vs. non-­‐CF chromosomes? (2 POINTS) c. In no more than two sentences, what does this figure suggest about the relationship between the ΔF508 mutation and cystic fibrosis? What conclusion can you draw and why? (4 POINTS) Page 13 of 17 NAME: __________________________________________________________ 25. This table is from a 1995 paper by Bellus et al looking at mutations in a gene implicated in achondroplasia. They presented both new mutation analysis and data from a previous study looking at specific mutations in the transmembrane domain of the gene. (5 POINTS TOTAL) a. In one sentence, what can you conclude from the data presented in this figure? (2 POINTS) b. What data are not presented in this figure that you might otherwise expect to see? Why are such data a critical part of an experiment? PLEASE ANSWER IN NO MORE THAN 2 SENTENCES. (Note: these data are presented elsewhere in the paper.) (3 POINTS) Page 14 of 17 NAME: __________________________________________________________ 26. This table is from the 1993 identification of the gene for Huntington’s disease (HD) by the Huntington’s Disease Collaborative Research Group. The gene implicated in HD has a polymorphic trinucleotide repeat. The authors compared the number of trinucleotide repeats seen in normal chromosomes to the number of trinucleotide repeats seen in HD chromosomes. (6 POINTS TOTAL) a. In one sentence, what was the goal of this figure? (2 POINTS) b. In one sentence, what are the results of this analysis? Please be specific (give numbers). (2 POINTS) c. In one sentence, what do you conclude about trinucleotide repeat length and Huntington’s disease from this figure and why do you make this conclusion? (2 POINTS) Page 15 of 17 NAME: __________________________________________________________ 27. An association between a variant in the gene LIPC and age-­‐related macular degeneration (AMD) was reported by Neale et al in 2010. The LIPC variant associated with AMD is a functional variant in the promoter that influences LIPC expression and serum HDL levels. The minor (less common) allele of the LIPC variant increases HDL (“good cholesterol”) levels and has a protective effect on the development of both wet and dry AMD. In their study, Neale et al also for associations between AMD and other previously reported HDL genetic loci. (7 POINTS TOTAL) Chr, chromosome; position, base-­‐pair position in NCBI 36.1; HDL-­‐raising allele, allele reported in Kathiresan et al. (25) as the allele responsible for raising HDL; MAF, minor-­‐allele frequency; Z score, weighted average and direction of minor allele signal; meta P, Pvalue for the association between the minor allele and AMD; OR, odds ratio for the minor allele; 95% CI, confidence interval for the OR. a. In one sentence, explain why it’s a reasonable hypothesis that previously reported HDL genetic loci might be associated with AMD given the new association between LIPC and AMD. (2 POINTS) b. Given the data in this figure, what do you conclude about the association between AMD and previously reported HDL genetic loci – do you see a consistent trend for association between these loci and AMD? Is there a difference in between HDL increasing or decreasing loci? What does this suggest about the mechanism of action of the LIPC variant identified by Neale et al? Explain your answer in no more than 3 sentences. (5 POINTS) Page 16 of 17 NAME: __________________________________________________________ 28. Neurofibromatosis type 1 (NF1) shows a great deal of clinical variability. Sabbagh et al (2009) studied the genetic component of the variable expressivity of the disease. As part of their study, they looked at five quantitative traits that are clinical features of NF1 and estimated the heritability of the traits. The table below is from their paper. (8 POINTS TOTAL) a. What is heritability? What does it tell us? Please answer in no more than 2 sentences. (2 POINTS) b. Looking at the data in this table, is there any evidence for a genetic contribution of the mutation in the NF1 gene itself? For which trait(s)? What indicates that? How strong is the evidence? Please answer in no more than 2 sentences. (2 POINTS) c. Which trait(s) have the strongest evidence for genetic effects? What leads you to that conclusion? Please answer in no more than 2 sentences. (2 POINTS) d. Based on the data from this table, do you think there are likely to be genetic modifiers of NF1? Which trait would you study first and why? Please answer in no more than 2 sentences. (2 POINTS) Page 17 of 17