AP Syllabus focus:
‘Random mutations arise from errors in DNA replication or repair and from external factors such as radiation or reactive chemicals.’
Random mutations occur without regard to whether they benefit the organism. They originate when DNA is copied or fixed imperfectly, or when environmental agents chemically alter DNA bases or break the DNA backbone.
What “random” mutation sources means
Mutations are “random” in origin because the underlying molecular events happen by chance, not because a cell “needs” a particular genetic change.
Mutagen: A physical or chemical agent that increases the probability of DNA sequence changes by damaging DNA or interfering with accurate DNA replication.
Mutagens do not direct which gene will change; they only raise the likelihood that errors will occur at susceptible sites.
Internal (endogenous) sources: replication and repair errors
Errors during DNA replication
Even with proofreading, DNA polymerases occasionally introduce incorrect bases.
Mispairing during base addition
Rare base tautomer forms can temporarily alter hydrogen bonding, leading to incorrect pairing (e.g., an A-like base pairing with C).
Replication slippage (especially at repeats)
Short tandem repeats can misalign, creating small insertions or deletions when the new strand “loops out.”
Damage encountered during replication
If the template contains an unrepaired lesion, polymerase may stall and a bypass polymerase may copy across it with lower accuracy.
Errors introduced during DNA repair
Repair systems usually restore the correct sequence, but mutations can arise when:
Damage is repaired incorrectly
Mismatch repair recognizes a mispaired base after replication, removes a segment of the newly synthesized strand containing the error, and fills the gap using the intact template strand. Failure or mis-targeting of this process can convert a transient mispair into a permanent mutation. Source
Mismatch repair can fail to detect an incorrect base or may replace the wrong strand section.
Error-prone lesion bypass occurs
Translesion synthesis polymerases can insert a nucleotide opposite a damaged base to keep replication moving, but with elevated error rates.
Double-strand break repair is imprecise
Non-homologous end joining can rejoin broken ends with small insertions/deletions, especially when ends are processed before ligation.
Spontaneous chemical changes inside cells
Normal cellular chemistry can modify DNA bases without any external exposure.
Depurination: loss of A or G bases creates an abasic site that can be miscopied.
Depurination removes a purine base (A or G), leaving an abasic site in the DNA backbone. During replication, polymerase may insert an incorrect nucleotide opposite the missing base, fixing a mutation in the daughter strand if the lesion is not repaired. Source
Deamination: C can deaminate to U, altering pairing properties if not corrected.
Oxidative damage: reactive oxygen species generated by metabolism can change bases (commonly G), increasing mispairing during replication.
External (exogenous) sources: radiation and reactive chemicals
Radiation
Ultraviolet (UV) radiation
UV light can covalently link adjacent pyrimidines on the same DNA strand, producing cyclobutane pyrimidine dimers (CPDs) and 6–4 photoproducts. These lesions distort normal base geometry and can promote misincorporation during replication if not repaired. Source
Promotes covalent bonds between adjacent pyrimidines (often T), distorting the helix and increasing misincorporation if unrepaired.
Ionising radiation (X-rays, gamma rays)
Produces DNA strand breaks and base damage (directly or via free radicals); misrepair can generate mutations and larger chromosomal changes.
Reactive chemicals
Different chemical classes raise mutation rates by altering bases or DNA structure.
Alkylating agents
Add alkyl groups to bases, changing pairing behaviour (e.g., promoting G to pair with T).
Base analogues
Mimic normal bases but pair differently some of the time, increasing substitution errors during replication.
Intercalating agents
Insert between base pairs, causing polymerase to add or skip nucleotides, often producing insertions/deletions.
Crosslinking agents
Form covalent links within or between strands, blocking replication; mutations can result if bypass or repair is inaccurate.
Key idea for AP Biology
Random mutations arise from (1) errors in DNA replication or repair and (2) external factors such as radiation or reactive chemicals. Natural selection acts on the outcomes, but it does not cause the mutations.
FAQ
Random refers to lack of goal, not equal probability everywhere. Some sequences are inherently less stable.
Factors include:
Repetitive DNA that promotes strand slippage
Methylated cytosines that are more chemically unstable
DNA secondary structures that stall replication
Cells use checkpoint signalling proteins that sense stalled replication forks and DNA breaks.
This can:
Pause the cell cycle to allow repair
Recruit repair enzymes to specific lesions
Trigger apoptosis if damage is extensive
No. Many lesions are “pre-mutational” and only become fixed as mutations after DNA replication.
Outcomes depend on:
Timing of replication after exposure
Which repair pathways act first
Whether the lesion is accurately repaired
ROS production depends on metabolic rate, oxygen exposure, and inflammation.
Higher ROS can occur with:
High mitochondrial activity
Chronic immune responses
Reduced antioxidant capacity
Different chemicals can converge on similar DNA lesions or replication consequences.
For example:
Distinct agents may both increase mispairing leading to the same base substitution
Multiple agents can stall replication and increase reliance on error-prone bypass pathways
Practice Questions
State two sources of random mutations in DNA. (2 marks)
Error during DNA replication or proofreading (1)
Error during DNA repair OR exposure to radiation OR exposure to reactive chemicals/chemical mutagens (1)
Explain how UV radiation and chemical mutagens can increase the rate of random mutations. (5 marks)
UV can form pyrimidine (e.g., thymine) dimers that distort DNA (1)
Distortion can cause incorrect base pairing during replication if not repaired correctly (1)
Chemical mutagens can alter bases (e.g., alkylation) and change pairing properties (1)
Chemical mutagens can intercalate and cause insertions/deletions via replication errors (1)
Mutations are random in origin (mutagens raise probability; they do not direct beneficial changes) (1)
