PHAR5350 Coursework

PHAR5350 Coursework – Report

(All Tasks must be performed INDEPENDENTLY)

You should perform the two mini projects and submit them as a single Word document or pdf containing your results (copied information or screen grabs of text / alignments / images) with a discussion of the methods and parameters chosen where appropriate. Note – be selective about the data you show.

Once completeyou should submit your work electronically via the turnitin link “report” in the “Assessment and feedback” folder on the PHAR5350 blackboard shell by the deadline stated.

IMPORTANT NOTE WHEN SUBMITTING TO TURNITIN When submitting your assignment via Turnitin on Bb you will need to follow the online instructions carefully to ensure that the assignment has actually been submitted.  This involves selecting your file and clicking on ‘upload’. You will then be asked the question: ‘Please confirm that this is the file that you would like to submit.’ Click on ‘CONFIRM’ to complete the process. You are strongly advised to keep a copy of the digital receipt by saving/printing a screen shot and keeping with your records in the event of any query regarding your submission. If you do not see a digital receipt then you have not submitted! The module leader will inform you if there are any technical problems with Turnitin at the time of submission and alternative instructions will be made available. Individual technical problems will not be accepted as an excuse for late submission. 24 hour technical assistance is available: http://www.dmu.ac.uk/dmu-students/student-resources/it-and-media/24-hour-support.aspx

Your submission should include your p number in footer of your word file and should also contain your p number in the name of the file itself but should not contain your name as this submission will be marked anonymously. You do NOT need to submit a printed copy of your work.

The deadline for submission of the report is 12 noon on the 15^th Aug 2020.

Task 1 – Dr Webb (50 marks)

1. Simvastatin is used to prevent cardiovascular disease.
   1. Identify the gene identifier and name of the pharmacodynamic target of this medication.
   2. Interrogate the PharmGKB database for information on variations present in this pharmacodynamic target. List the variations you identify.
   3. Use the GWAS catalog to determine if the gene you identified in 1a have been associated with a phenotypic response in genome wide association studies. List the variations you identify.
   4. Produce a summary Table for each of the variations you have identified in 1b and 1c from the information available in for them in their GWAS catalog and dbSNP entries, (this should include comment on any population diversity information that is available).

2. Investigate the small nucleotide polymorphisms database (dbSNP) for variations in the gene you identified in question 1a:
   1. How many variations are present in total?
   2. How many polymorphisms result in a missense alteration?

For the first variation you identified in 2b access the variation viewer and identify how many variations are located within ~ 250 bases of it in the GRCh38.p12 assembly (annotation release 109).

1. Create a table that summaries the variation types found in this region and their molecular consequences.
2. Create a table that summarises the information for any variations that have a pathogenic clinical significance.

3. Using the genome variation server, identify tag SNPs for the pharmacodynamic target gene for Simvastatin you identified in question 1a that are located within 10,000 bases upstream and downstream of the gene and are common to ALL of the HAPMAP panels an r² value of 0.8 and an allele frequency of 20%
   1. How many SNPs are common to these populations?
   2. Identify the Tag SNPs need to cover this region of the genome for all the populations and for the population subgroups
   3. Repeat the analysis with the r² at 0.8 and allele frequency altered to 10%. Describe the effect this change has on the results and explain why it does so.

4. You are required to design a test to personalise the treatment of hyperlipidemias with Simvastatin.

1. Consider the variations you have identified for question 1 and 2. Discuss which would you include in the test?
2. Perform a literature search to identify additional variations for inclusion.
3. Provide a critical evaluation of whether there are any population groups that the test results would be most beneficial for?

Task 2 – Dr Smith (50 marks)

Sequence 1:

MWPGILVGGARVASCRYPALGPRLAAHFPAQRPPQRTLQNGLALQRCLHATATRALPLIP

IVVEQTGRGERAYDIYSRLLRERIVCVMGPIDDSVASLVIAQLLFLQSESNKKPIHMYIN

SPGGVVTAGLAIYDTMQYILNPICTWCVGQAASMGSLLLAAGTPGMRHSLPNSRIMIHQP

SGGARGQATDIAIQAEEIMKLKKQLYNIYAKHTKQSLQVIESAMERDRYMSPMEAQEFGI

LDKVLVHPPQDGEDEPTLVQKEPVEAAPAAEPVPAST

1. You have been provided with a sequence of a human protein (above).

1. Identify what the sequence is and discuss its function.
2. Prepare a multiple sequence alignment of sequence 1 with other similar sequences in different organisms.
3. Using your multiple sequence alignment, produce a phylogenetic tree. In your answer, consider adding an outlier to help with rooting. Discuss your findings.

2. The next tasks are centred around the human cytochrome P450 genes, with particular focus on CYP2D6.

1. Determine the phylogenetic relationships between members of the human CYP2 family. In your answer, you should consider the below points:

1. Search strategy for genes in the human CYP2 family
2. Multiple alignment of CYP2 sequences
3. Optimisation of alignment, if required
4. Selection of alignment regions for phylogenetic analysis
5. Phylogenetic analysis using suitable method(s)
6. Visualisation of the phylogeny as a phylogenetic tree

1. Compare the two following studies of gene expression profiles in normal human tissues on the NCBI GEO site. In your comparison, discuss the experimental design and consider the platforms and the number and range of samples used.
   1. Series GSE7905
   2. Series GSE2361

1. Determine the expression profile of CYP2D6 in normal human tissues using the above two series.
   1. In which tissue is CYP2D6 expression most prominent?
   2. How similar are the results from the two studies?

1. Compare and discuss the expression profile of CYP2D6 from these two studies with that shown in the 53 GTEx RNA-Seq study in the EBI Gene Expression Atlas.
   1. Based on what you know of its function, are these results to be expected?

Assessment and feedback

The assessment criteria for each of the mini projects are:

Criterion	Descriptor	Marks available
Technical competence	Ability to successfully perform the tasks using an appropriate methodology	15
Appropriate evidence	Relevance of supporting evidence	10
Response to questions / Critical Analysis	Appropriate data extraction, accurate answers to the questions, correct interpretation and evaluation of the data set	25

Mini project tasks will be marking with reference to the marking scheme for postgraduate taught course (page 5).

Feedback for the assessment will be posted on the blackboard shell via grademark within 20 working days of the submission date.

Postgraduate Taught Course Marking Descriptors

Mark Range	Criteria
90-100% Distinction	Demonstrates an exceptional ability and insight, indicating the highest level of technical competence The work has the potential to influence the forefront of the subject, and may be of publishable/exhibitable quality. Relevant generic skills are demonstrated at the highest possible standard.
80-89% Distinction	Demonstrates an outstanding ability and insight based on authoritative subject knowledge and a very high level of technical competence. The work is considered to be close to the forefront of the subject, and may be close to publishable/exhibitable quality. Relevant generic skills are demonstrated at a very high level.
70-79% Distinction	Demonstrates an authoritative, current subject knowledge and a high level of technical competence. The work is accurate and extensively supported by appropriate evidence. It may show some originality. Clear evidence of capacity to reflect critically and deal with ambiguity in the data. Relevant generic skills are demonstrated at a high level.
60-69% Merit	The work is well developed and coherent; may show some originality. Clear evidence of capacity to reflect critically. Relevant generic skills are demonstrated at a good level.
50-59% Pass	Demonstrates a sound, current subject knowledge. No significant errors in the application of concepts or appropriate techniques. May contain some minor flaws. Demonstrates satisfactory subject knowledge. Some evident weaknesses; possibly shown by conceptual gaps, or limited use of appropriate techniques. The work is generally sound but tends toward the factual or derivative. Limited evidence of capacity to reflect critically. Relevant generic skills are generally at a satisfactory level.
40-49% Fail	Demonstrates limited core subject knowledge. Some important weaknesses; possibly shown by factual errors, conceptual gaps, or limited use of appropriate techniques. The work lacks sound development. Little evidence of capacity to reflect critically. The quality of the relevant generic skills do not meet the requirements of the task. Demonstrates inadequate subject knowledge.
30-39% Fail	The work lacks coherence and evidence of capacity to reflect critically. The quality of the relevant generic skills do not meet the requirements of the task. Demonstrates seriously inadequate knowledge of the subject.
20-29% Fail	The work contains minimal evidence of awareness of relevant issues or theory. The quality of the relevant generic skills do not meet the requirements of the task.
10-19% Fail	The work is almost entirely lacking in evidence of knowledge of the subject. No evidence of awareness of relevant issues or theory. The quality of the relevant generic skills do not meet the requirements of the task.
0-9% Fail	The work presents information that is irrelevant and unconnected to the task. No evident awareness of appropriate principles, theories, evidence and techniques.