ProblemSet03 - BC367, Fall 2011 Problem set #3 Due: Friday,...

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Unformatted text preview: BC367, Fall 2011 Problem set #3 Due: Friday, September 23 “Protein homology searching – a case study” The situation: An adult male presents with fatigue and shortness of breath when physically active. He is anemic and has a pale complexion. He has discomfort on the left side of his abdomen from an enlarged spleen. He is also experiencing excessive sweating, weight loss, and inability to tolerate warm temperatures. Genetic tests reveal a chromosomal abnormality and a DNA sequence that, base for base, has not previously been reported. The sequence translates into the following linear polypeptide sequence. VHSIPLTINKEDDESPGLYGFLNVIVHSATGFKQSSKALQRPVASDFEPQ GLSEAARWNSKENLLAGPSDNDPNLFVALYDFVASGDNTLSITRGEKL RVLGYNHNGEWCEAQTKNGQGWVPSNYITPVNSLEKHSWYHGPVSRN AAEYLLSSGIN Procedure: 1) Read the Sequence Similarity Searching information web page. 2) Go to the BLAST home page. 3) Select “Protein BLAST” link. 4) Cut and paste the above polypeptide sequence into the search field (labeled “Enter accession number, gi, or FASTA sequence”). Ensure that the search set is the non‐ redundant protein sequences database. Enter ‘human’ in the organism field. Change no other parameters 5) Click “BLAST”. 6) The first thing you’ll see is a graphical representation of the search results – the red bars show highly conserved matches. Rolling your mouse over the bars will identify the matched sequences. Scroll past the long list of all matching sequences until you reach the actual sequence alignments. Questions (a few sentences to a small paragraph each … TYPED!): 1) Look carefully at the first few aligned sequences. The ‘Query’ sequence is the one you entered – the ‘Sbjct’ sequence is the one from the database to which your sequence is being compared – the sequence between the two is a composite. Scan the alignment and identify the differences. What are the mutations and how do they compare at the amino acid level? Are these mutations likely to result in a dramatic functional difference among the query sequence and the subject sequences? Explain. 2) Click on the GENE ID links of the first few alignments. The complete database entries for each sequence should appear. What kind of information do you see? What kind of protein does our sequence likely come from? What is the significance of identification with respect to the patient in this study (you should use other sources of information for this question)? 3) Click on the ‘Pubmed’ link towards the bottom of one of the GENE ID pages. Scan the titles of the journal articles and read some of the corresponding abstracts. Based on what you saw in the GENE ID pages and these titles, what is the likely diagnosis for our patient? Copy and paste the complete name of the disease given in the abstract title into the search field on top of the PubMed page. Add the search term ‘therapy’ and click ‘search.’ By inspecting the titles and abstracts of the journal articles that you see, what is the latest in current clinical research with this disease? What does the future hold? 4) Now add the search terms ‘imatinib’ and ‘resistance’. What is imatinib? What are dasatinib and nilotinib? Speculate as to which agent might be the better therapeutic option for our patient? 5) Repeat the same BLAST search, but with ‘mouse’ as the organism. Identify sequence differences as before. Would the mouse be an appropriate model organism to study potential therapies for our patient’s disease? Explain. ...
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