UNIVERSITY OF YORK BA, BSc, and MSc Degree Examinations

Transcription

1 Examination Candidate Number: Desk Number: UNIVERSITY OF YORK BA, BSc, and MSc Degree Examinations Department : BIOLOGY Title of Exam: Human genetics Time Allowed: 2 hours Marking Scheme: Total marks available for this paper: 100 Sec on A: Short Answer / Problem / Experimental Design ques ons (50 marks) Sec on B: Essay ques on (marked out of 100, weighted 50 marks) The marks available for each ques on are indicated on the paper Instructions: Sec on A: Answer all ques ons in the spaces provided on the examina on paper Sec on B: Answer either ques on A or ques on B. Write your answer on the separate paper provided and a ach it to the back of the ques on paper using the treasury tag provided. Materials supplied: CALCULATOR For marker use only: For office use only: Module total as % DO NOT WRITE ON THIS BOOKLET BEFORE THE EXAM BEGINS DO NOT TURN OVER THIS PAGE UNTIL INSTRUCTED TO DO SO BY AN INVIGILATOR page 1 of 12

2 SECTION A: Short Answer / Problem / Experimental Design questions Answer all questions in the spaces provided Mark total for this section: a) The population size of humans is more than four orders of magnitude greater than that of chimpanzees and gorillas. However, the genomes of chimpanzees and gorillas contain much greater genetic diversity compared to human genomes. How can you explain this unexpected pattern? (3 marks) A study genotyped humans from 10 east Asian populations at 50,000 autosomal SNPs. In the figure below, a) shows the location of the genotyped populations. Genetic diversity, measured as heterozygosity, was calculated for each of the populations and are plotted against latitude in b). page 2 of 12

3 b) What processes are likely to be responsible for the latitudinal gradient in genetic diversity across the 10 east Asian populations. (3 marks) 2. a) One sign of recent positive selection acting on a section of a genome is extended tracts of homozygosity flanking the genetic variant under selection. Explain why these extended tracts of homozygosity develop as a result of recent selection. (5 marks) page 3 of 12

4 The figure below shows tracts of homozygosity flanking the lactase-persistence associated SNPs in African (top panel) and Eurasian (bottom panel) populations. Each horizontal line depicts a single individual; African lactase-persistent individuals (red), African non-persistent individuals (blue), Eurasian lactase-persistent individuals (green), Eurasian non-persistent individuals (orange). Note that some homozygosity tracts are too short to be visible as plotted. b) Describe any differences in the homozygosity tracts between African and Eurasian lactase-persistent individuals. (2 marks) page 4 of 12

5 c) From these differences, what can you infer about the evolution of lactase persistence in these populations? (3 marks) The space above this line should be sufficient for your answer page 5 of 12

6 3. The figure below shows the results of a genome-wide association study in which 297,086 polymorphic SNPs were genotyped in samples from 1522 case subjects with rheumatoid arthritis and 1850 control subjects. The blue horizontal line indicated with the arrow shows SNPs that are significant at a genome-wide level after Bonferroni correction (P < 5 x 10-8 ). SNPs at three loci ( PTPN22, MHC and TRAF1-C5 ) appear to be associated with the disease. a) What other lines of evidence are required to ascertain the validity of these SNPs associated with the disease? (4 marks) b) Any associations with P > 5 x 10-8 have been ignored. Discuss whether or not this is appropriate. (4 marks) page 6 of 12

7 4. In a recent study, linkage of a non syndromic mental retardation mutation was attempted from a single family (MR-D). The LOD score table below was obtained using two markers around candidate gene TUC3. Haplotype analysis with additional markers from the region was then carried out and the results are shown on the pedigree. a) What is the pattern of inheritance in family MR-D? (1 mark) b) Was haplotype analyses with further markers from the same region an appropriate strategy to follow? Briefly justify your answer. (1 mark) page 7 of 12

8 c) If a mutation in TUC3 was responsible for this condition, would you expect the haplotypes obtained? Briefly explain. (2 marks) d) What experimental approach would be most feasible to apply in this case? Briefly explain. (2 marks) The space above this line should be sufficient for your answer page 8 of 12

9 5. The pedigree A shows segregation of a dynamic repeat expansion causing a neurodegenerative disease in a Chinese family (American Journal of Medical Genetics 141B: (2006)). B shows the results of a PCR amplification with primers flanking the expansion for generations II and III individuals. Individuals from generation II range from 50 to 65 years. All individuals from generation III are less than 30 years old. a) What is the most likely pattern in inheritance. Explain. (2 marks) b) Why is III-5 the only individual from generation III showing symptoms? (2 marks) c) What would be the most likely outcome (affected or unaffected) later in life for: (1 mark) III-1: III-4: page 9 of 12

10 6. Myotonic dystrophy (DM) is caused by an unstable CTG trinucleotide repeat in the 3 untranslated region of the dystrophia myotonica protein kinase (DMPK) gene, which is pathogenic when above 35 repeats. Segregation of this disease in a family is shown (Amiel et al, J Med Gen 2001). Each haplotype shows in brackets the length of the repeat for both alleles. (Fetus III.3 was genotyped using chorionic villus sampling.) a) What is the pattern of inheritance? (1 mark) b) Which haplotype bears the causative alleles? (1 mark) c) Would you anticipate individual III.3 to show the disease later in life? Explain. (3 marks) page 10 of 12

11 7. The pedigree below shows a family with severe X-linked Haemophilia A segregating. Linkage analysis was used to establish the carrier status of II:3 with an RFLP located 15 cm from the mutation. The genotype results are shown on the pedigree. What is the risk of II.3 being a carrier? (10 marks) Probability II.3 Is a carrier II.3 Is Not a carrier Prior Conditional: 3.7Kb allele 1 normal son Joint Posterior page 11 of 12

12 SECTION B: Essay question Answer one question on the separate paper provided Remember to write your candidate number at the top of the page and indicate whether you have answered question A or B Mark total for this section: 50 EITHER A) Discuss what the composition of the human genome can tell us about our evolutionary history. OR B) Discuss the benefits and challenges of discovering rare disease-causing mutations in the era of next generation sequencing. page 12 of 12