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02­250: Introduction to Computational Molecular Biology

02­250: Introduction to Computational Molecular Biology

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Author: Minnie Fisher
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02­250: Introduction to Computational Molecular Biology Spring 2016, Homework 5, Your name:Your gene: bRAF Choosing model organism is a complex task, some of the part we did before usingthe protein sequence similarity. Let evaluate the possible model organisms from thewhole genome view. Particularly taking into account that practically no one gene actalong, on contrary usually there is a cluster of genes working together, and in many casesthey are located close to each other on the genome. Let’s do some research to find outabout other genes related to your gene and the disease it involves.1. (1 pts) Locate your gene in human genome, choose the latest build. On whichchromosome and over which positions it is found?2. (2 pts.) Which genes lie within close distance of the your gene? Find at least 10 closelylocates genes. Find an image of the genome in that region showing the gene locations.List all the genes.3. (5 pts) Explore each gene. Based on the known functions of these genes, which wouldbe the most plausible candidate(s) for the disease associated with your gen, and can bealso a target for the mutation and why? There can be several, depending on therefunctional relations to the disease and to your gene; choose best two. These genestogether with your gene will be your test set.4. (3 pts) Evaluate the quality of each gene in your test set. How was the intron/exonstructure of these genes determined? Given your answer, should we have high confidencethat the gene’s structure is annotated correctly? (Hint: The mapview entry for the mRNAsof the gene will have details about the source of the sequence.)5. (4 pts) Using genome browser (UCSC Genome Browser will be better for this task)identify best model organism, which can represent all the genes in your test set and alsointergenic regions. Locate every gene from your selected list in the genomes and plot theregion, setting the “RefSeq Genes,” “Other RefSeq,” “N­SCAN,” and “Conservation”tracks to “full”. (Hint: The resulting pictures for each gene may look like the one on thelecture slide with conservation.)6. (3 pts) We would expect that introns will evolve more quickly than exons, andtherefore we can find likely exon positions by looking for more conserved nucleotides.Based on your plot for problem 5, does conservation within the organisms at the baselevel provide support for the specific exon locations in the gene model? Why or why not?7. (1 pts) Again looking at your plot from problem 5, what organism provides the bestevidence from conservation for or against the specific human gene structure model? 8. (2 pts) Based on the conservation you can observe here, roughly when in the evolutionof modern organisms does the exon structure appear to have emerged for this gene? (Forexample, did it emerge after primates separated from other mammals but before monkeysdiverged from great apes? Did it emerge after placental mammals separated frommarsupials but before primates separated from other placental mammals?) Justify youranswer in a sentence or so by reference to evidence from the conservation of the geneacross species.9. (3 pts) If we suspect that the genes in your test set might be alternatively spliced, thenwe can look for evidence in other organisms for alternative splicing of the homologousgene. Use one organismas a more distant homolog for which good experimental data islikely to be available. How many experimentally observed splice forms are there for yourgenes in this organism? Do they correspond well with the exon model annotated for thehuman gene? If available, please use the model organism database.10. (1 pts) We might decide that the best way to resolve the true splice form(s) is to doour own sequencing of the model transcriptome and see mRNAs appear for this gene andwhat models they support. Suppose we have the option of using an Illumina sequencer ora 454 sequencer. What would be the relative advantages and disadvantages of each forthis purpose? -Bonus question (4 pts) Using available resources identify new genes related to thedisease, your gene related to, but located not in close proximity like in the aboveexercise, but in other place(s) and may be even in other chromosomes. You can useeither human or model organisms or both. Provide convincing evidence.


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