BIOL3204 - Genetics of Human Disease Assignment

Assignment Task

Questions

1. a. For each of the following single nucleotide variants listed in the table below, determine the change to codon sequence, classify the variant and mutation type, and give the protein sequence nomenclature for the variant.

Codon change: normal > mutation.

Variant type: synonymous or nonsynonymous.

Mutation type: missense, nonsense or silent.

Protein sequence: give 3-letter and 1-letter codes.

b. In what region of the CFTR gene are these SNVs located: exon 1, intron 1, or the 5`UTR?

c. Complete the information in the following table for the CFTR gene

• Cytogenetic location
• CDS accession number
• CDS length (bp)
• Genome region size (bp)
• GRCh38 Genome region (chromosome-start-stop bp)
• Ensemble canonical transcript ID
• Ensembl gene IDNumber of pathogenic mutations (ClinVar)

2. In the practicals you studied two different CFTR variants, F508del and W1282X, which are both known to cause CF.

a. Using your answers and the websites you accessed during the process, summarise the information about these variants by completing this table.

b. What proportion of CF patients (in the CFTR2 registry) are compound heterozygotes for these variants? 

c. Why do you think there are differences in the frequency of mutations found in the CFTR2 and Australian CF registries?

3. a. Another relatively common disease-causing CFTR variant is G551D. Consult peer-reviewed publication(s) and gene variant databases to complete the following table summarising this mutation.

• CFTR mutation class
• Effect on CFTR expression
• Effect on CFTR expression
• Effect on CFTR apical cell membrane levels
• Effect on Cl^- ion channel conductance
• Effect on ATP binding and hydrolysis
• Proportions (to nearest 1 d.p.) of CFTR2 registry and Australian cases that have this mutation
• Highest allele frequency, carrier population, and database source (including genome and exome).
• Overall exome and genome allele frequencies
• Publications used for your answers

b. Discuss factors in the source data that can explain why the exome and genome G551D allele frequency values are not the same, and why one source may be considered more accurate than the other.

c. The G551 site in CFTR is said to be multi-allelic. Explain what this means.

d. Identify all the known alleles for G551, and the variant ID and pathogenicity prediction.

• Protein denotation
• Variant ID
• Pathogenicity

e. Despite its multi-allelic status of G551, do you agree that only the 7-117587806-G-A variant should be routinely tested as a likely cause of CF?

4 . In Practical 2 you learned about the Fort Lauderdale Agreement and its three underlining principles (Bermuda Principles). There are three main constituencies within the scientific research community that share the responsibilities of upholding this agreement.

List the types of people and/or organizations that would identify with each constituency.

Types of people and organizations that identify with this group

• Resource producers
• Resource users
• Funding agencies

b. Under these agreements (FLA), donated tissue, once it has been made anonymous, may end up as public property with the donor having no knowledge or control over it. Some people, however, think that the individuals who have donated the tissues should be informed about what their tissue donation is being used for and that their consent should be required. What do you think? Provide reasoning for your position.

5. To complete this assignment question, you’ll need to have completed or least understand how to complete Question 17 in Practical 3. It considers another severe genetic disease with a recessive mode of inheritance which in Australia can be screened using a genetic test (comparable to cystic fibrosis), but which has a different carrier frequency and testing accuracies, as follows:

• 5 % of the population are carriers of mutation causing a recessive condition.
• In 20% of tests this genotyping chip fails to detect a carrier.
• In 2% of tests this genotyping chip falsely indicates that someone is a carrier when they are not a carrier.

a. Calculate the values indicated in the table and show your working below, similar to what you presented in the Practical.

b. The genotyping chip produces more false positive results than false negatives, despite having a very high specificity (true negative rate) but a low sensitivity (true positive rate). Can you explain why this finding seems counter-intuitive?

6. Table 1 shows the 2021 data on the 10 most common CF variants in Australia among 3496 patients. Table 2 shows the most common alleles that are found as compound heterozygous with F508del. Use these tables to answer the following questions.

Calculate the number of individuals that are compound heterozygous for F508del and then use this information to determine the number of patients that carry the F508del allele. 

a. What is the frequency of the F508del allele in the CF patient population?

b. Calculate the expected proportion and number of homozygous W1282X individuals in the CF patient population as well as the observed proportion, and explain why the expected and observed rates are not the same.

c. In Practical 3 you learned that the results of the genotyping chip indicate that Naomi carries only one CF-causing mutation, W1282X. List at least FOUR possible explanations for the discrepancy between Naomi’s diagnosis of CF and detection by the test of only one CF-causing mutation.

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