Molecular genomic epidemiology of infections

Question 1

What types of mutations are there?

Answer 1

1. Silent: Mutations that are intragenic (between genes)
   or Synonymous (not altering coding)
2. Non-Synonymous: Substitutions causing coding to be altered
3. Corruptive: Deletions or Insertions (disrupting coding frame)
   → Creation of STOP codons (truncation)
   → Corruption of STOP codons (elongation)
   → Corruption of CONTROL sequences (eg. promoters)

Question 2

What is drift? What is antigenic drift?

Answer 2

→ Gradual alteration in sequence is called DRIFT.
→ Some mutations have more influence on Ab
binding affinity than others
→ Herd immunity (after large vaccination program)
kills most but also selects for escape mutants that
maintain the drift

→ Antigenic drift is the same antigen changing its sequence base by base
→ Antigenic shift is a sudden replacement of an antigen by recombination with another viral type that has evolved separately (either in another animal or another human population)
→ New types will not be protected against by previous infection or vaccination - leading to new epidemics

Question 3

What factors can affect the speed of the ‘molecular clock’ in regards to mutation rate?

Answer 3

1. Bacterial replication rate: A high division rate provides a higher mutation rate
2. DNA or RNA polymerase proof reading fidelity:
   Some species (eg HIV) have low fidelity promoting high mutation rate
3. Selection pressure from the host or environment:
   → High selection pressure removes ‘weak’ mutants and emphasises clusters
   → Loss of selection pressure allows deletions
4. Degree of redundancy in the genome:
   → Multiple copies of a single gene in the genome allow for mutations in one copy without compromising overall functionality
   → Movement or recombination within genome may not effect phenotype
5. Transmission rate:
   High transmission rates relative to the mutation rate
   results in dissemination and single strain outbreaks
   (Flu A = 2-3 bases per year and 1.5 transmissions per infection)

Question 4

Which genes change the most in mutations?

Answer 4

→ Hyper-variable genes change more rapidly than conserved genes
BUT
→ Conserved genes are more likely to be associated with phenotype and virulence

→ Not all changes are new, some may revert BACK to an older profile (convergent evolution)

→ Large and rapid changes are rare but often lead to escape from existing herd protection
→ Some genes could be replaced completely!
(Antigenic SHIFT)