Mechanisms of Spontaneous DNA Mutations

Deamination

Deamination is the loss of an amino ($\text{NH}_{2}$) group from a nucleotide base. While various bases can undergo this process, the deamination of cytosine is the most significant event regarding mutation frequency.

When cytosine undergoes deamination, it is converted into uracil.

Under normal circumstances, DNA mismatch repair systems recognize uracil as an inappropriate base in DNA (since uracil is typically found in RNA) and restore the original cytosine. However, if the repair fails and the cell replicates, the uracil will pair with an adenine, eventually leading to a permanent $C-G$ to $T-A$ transition mutation.

Exam Tip: Remember the distinction between damage and mutation. Depurination and deamination create DNA lesions (damage). These only become mutations if they are not repaired before the next round of DNA replication.

Replication Errors

Even when the DNA template is chemically intact, the process of copying the genome can introduce errors.

DNA Base Mispairing and Incorporated Errors

During DNA replication, the polymerase may occasionally select the wrong nucleotide, leading to DNA base mispairing. These are known as incorporated errors.

If the polymerase incorporates a base that does not correctly pair with the template (for example, pairing a $G$ with a $T$), the error is not yet a permanent mutation. It only becomes a permanent base substitution mutation after the cell undergoes a subsequent round of replication, where the mispaired base serves as a template for a new, incorrect partner.

Strand Slippage and Repeat Expansions

Another mechanism of error is strand slippage, which occurs when the DNA polymerase "slips" while replicating repetitive sequences. This typically happens in regions containing many identical, consecutive nucleotides.

When the newly synthesized strand or the template strand loops out during replication, it can result in the insertion or deletion of repeat units. This mechanism is the primary driver behind trinucleotide repeat expansion disorders. In these disorders, the slippage leads to a progressive increase in the number of repetitive sequences, such as CAG triplets, within the genome.

Summary of Mutation Mechanisms

The following table summarizes how different spontaneous events lead to permanent changes in the genome: