DNA Damage & Mutation Flashcards
Define DNA damage
A change to regular structure of DNA double helix [premutagenic]
Define mutation
A permanent heritable change in sequence of organisms genome [structure is normal]
If damaged DNA is replicated before it is repaired, what can this lead to?
Mutation
How does the eukaryotic spontaneous mutation rate vary?
Varies across different sequence classes
Varies in different tissues throughout body
Somatic mutation rate is higher than germline mutation rate
Germline nucleotide subsitution is about 10^-8 /nucleotide per generation (30 new mutations in 3 Gb haploid genome from each parent)
What is the spontaneous mutation rate of prokaryotes?
For a 1kb gene, 1 mutation per 1 million cell divisions
What is the adaptive mutation model?
Organisms ‘direct’ mutations to adapt to a particular environment (Lamarckism)
What is the random mutation model?
Changes/mutations occur by chance and sometimes happen to be adaptive
If the adaptive mutation model was correct, what results would we expect to see from a resistance to T1 phage experiment?
T1 phage resistance, after adding T1 phage to a culture, should occur in similar percentages each time the experiment is undertaken
If the random mutation model was correct, what results would we expect to see from a resistance to T1 phage experiment?
T1 phage resistance, after adding T1 phage to a culture, should occur in different percentages each time the experiment is undertaken
What are the mechanisms used during replication to ensure fidelity of DNA synthesis?
What is the frequency of errors that escape past each point?
What is the overall rate of mis-incorporated nucleotides not repaired?
Base pairing (1 error in 10 - 100)
DNA polymerase [active site and proofreading] (1 error in 10^5 -10^6)
Accessory proteins [SSB] (1 error in 10^7)
Post replication mismatch repair (1 error per 10^9 - 10^10)
So overall rate of mis-incorporated nucleotides not repaired: 1 error per 10^9 - 10^10
How can tautomers lead to mutation?
Tautomers form non Watson-Crick base-pairs, so the incorrect nucleotide is incorporated, resulting in a mismatch.
If mismatch is not repaired, after another round of replication one of the 2 resulting DNA helixes will have a permanent sequence change. [The other will be correct again].
Mammalian cells lose how many bases per cell per day due to depurination?
Mammalian cells lose 18,000 bases per cell per day!
Frequent damage, can be fixed before mutation
How many bases are deaminated per cell per day?
100-500 bases
What is the rate of base damage by ROS per cell?
2300 bases damaged per cell per hour
What accounts for the high mutation rate in mitochondrial genomes?
Attack by reactive oxygen species (ROS)
