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MIT 7 012 - Problem Set 7

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NAME_____________________________________________________________TA__________________ SEC____7.012 Problem Set 7 FRIDAY December 3, 2004Not due unless you have had a prior agreement with Claudette Gardel Solutions will be posted on the web.Question 1Leukemia is type of cancer characterized by the uncontrolled proliferation of white bloodcells (leukocytes). Chronic Myelogenous Leukemia (CML) is a type of leukemia primarilycaused by a translocation that relocates an oncogene, called abl, from the long arm ofchromosome 9 to the long arm of chromosome 22 in the bcr region (breakpoint clusterregion). The resulting bcr-abl fusion protein encodes a constitutively active tyrosinekinase, which when expressed, leads to the CML phenotype.a) Gleevec is an effective drug treatment of CML. What design principles were applied tothe development of Gleevec? How is this approach different from that used to developconventional cancer therapies?b) How does Gleevec work at the molecular level?c) How many protein targets does Gleevec have? Name each target.d) Besides target specificity, what other characteristics of a drug should you considerwhen designing a therapy?MIT Biology Department7.012: Introductory Biology - Fall 2004Instructors: Professor Eric Lander, Professor Robert A. Weinberg, Dr. Claudette Gardel2In contrast to drug treatments, gene therapy attempts to correct the defect byintroducing a functional copy of the malfunctioning gene that is responsible for thedisease phenotype. The functional gene copy can be introduced directly into the diseasedorgan or can be used to genetically modify isolated tissue that is later re-introduced intothe patient.e) What do you need to know about the target disease in order to apply gene therapy?f) How could you deliver the functional gene into the diseased cells?g) What do you think are some of the challenges facing gene therapy?h) Based on your understanding of oncogenes, why would bcr-abl be a particularlychallenging target for gene therapy?3Question 2Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the geneencoding dystrophin, a protein involved in maintaining membrane integrity in muscle cells. The dystrophingene spans roughly 2.5 Mb and is spliced to form a 14 kb mRNA transcript consisting of 79 exons.a) Is dystrophin is a typical human gene in terms of its size and exon count?b) Why is DMD much more common in boys than in girls?c) The DMD phenotype results from mutations that disrupt the reading frame of the dystrophin mRNA.What is the impact of such mutations on the dystrophin protein?d) Based on what you know of dystrophin’s normal function described above, what do you think arecharacteristics of the DMD disease phenotype?The dystrophin protein contains several functionally distinct regions (domains). The N-terminal domaininteracts with proteins inside the muscle cell, while the C-terminal domain enables dystrophin to bind tomembrane-associated proteins. The long rod-like central part of the protein is composed of 24 identicalrod domains (internal repeats). As a consequence of the modular structure of dystrophin, proteins missingsome of the internal repeats can be fully functional or at least partly active.One therapeutic strategy involves excluding, or skipping, an internal exon during splicing. In particular,skipping the exon that contains the frame-shift mutation in the DMD individual can result in a shorter thanwild type but functional dystrophin protein. This exon-skipping therapy involves introducing a small RNAmolecule that is complementary to the exon to be skipped. Binding of the RNA to the pre-mRNA preventsproper recognition of the exon by the splicing machinery and results in specific exon skipping.e) In order for this therapy to work, what properties must this small RNA have? (Think aboutcellular localization.)f) How would you deliver the RNA molecule into the target cell?g) How is this therapeutic approach different from gene therapy?h) What challenges do gene therapy and exon-skipping therapy have in common?N-terminaldomainC-terminaldomain4Question 3a) What percentage of genomic nucleotides do you expect two randomly chosen people tohave in common?Genome sequencing has revealed that the average genome nucleotide difference betweentwo randomly selected chimpanzees is roughly four times greater than between twohumans. Based on population genetic theory, levels of genetic variation within species shouldcorrelate positively with population size. However, the human population numbers in thebillions and the population size of chimpanzees is fewer than a hundred thousand.b) How can you explain the comparatively little variation between human individuals?c) What is genetic drift?A few years ago, an international consortium was formed to uncover the locations ofgenetic variation in the human genome. In particular, the consortium worked to identifysingle nucleotide polymorphisms (SNPs) within the human population.d) Is the genomic variation between individuals randomly distributed across the genomeor does such variation occur at common sites?e) What is a haplotype?f) Why is an understanding of genomic variation useful for the study human health?Images removed due to copyright reasons.5Question 4Now that the first draft of the complete* genomic sequence of the Chicken is availableon the web (http://www.genome.ucsc.edu/cgi-bin/hgGateway?org=Chicken) you decide tostart analyzing the sequence.* except for the sex chromosomes! (We’re waiting on Winston for this.)Luckily, there are a lot of resources available. After all, Chicken is an important modelorganism for the study of viruses, cancer, and developmental biology (and it’s fingerlickin’ good…)a) Genbank (available from http://www.ncbi.nlm.nih.gov) lists 559394 mRNA sequencesderived from Chicken. Explain how you could use these sequences to find genes in theChicken genome.b) Does your method also provide information about the structure of genes (i.e.intron/exon boundaries, splice sites)? What are the possible limitations of your method?c) Now that you know the locations of all of the autosomal genes in the Chicken genome,you would like to start trying to predict regulatory sequences. Unfortunately, Chicken isthe only bird that has been sequenced. Why might this be a problem? How haveregulatory sequences been found in other organisms, such as yeast and mammals?d) You talk to Eric about your problem, and he offers to sequence 3 bird species to


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MIT 7 012 - Problem Set 7

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