DNA containing short repeated sequences can be unusually prone to changes in repeat number because the template and newly synthesized strands can temporarily align in more than one equivalent register.

This process is called replication slippage.

Consider a simple repeated sequence:

... CAG CAG CAG CAG ...

During replication, the new strand can briefly separate from the template and then re-pair one repeat unit out of alignment. Because neighboring repeat units have the same sequence, the misaligned structure can still contain substantial complementary base pairing.

A loop in the new strand can create an expansion

If the newly synthesized strand realigns backward, some newly copied repeat sequence can form an extra loop. If the loop persists and is copied in a later replication cycle, the descendant DNA can contain an additional repeat unit.

4 repeats → slippage → 5 repeats

This is a repeat expansion.

A loop in the template can create a contraction

If the template strand forms the extra loop instead, the polymerase can effectively skip one or more repeat units. The daughter sequence can then contain fewer repeats.

4 repeats → slippage → 3 repeats

This is a repeat contraction.

Repeats make misalignment easier

In a unique DNA sequence, shifting one strand by several nucleotides usually destroys complementarity. In a tandem repeat, several alignments can look locally plausible because the same sequence occurs again and again.

The probability of slippage generally depends on repeat length, repeat-unit sequence and the properties of the replication machinery.

Replication slippage therefore gives repeated DNA a distinctive mutation mechanism: copying can change how many repeat units are present without requiring a base substitution or a large chromosome rearrangement.