Insertions, Deletions, and the Frameshift Catastrophe

Adding and removing letters

An [[insertion|insertion]] adds one or more bases to the sequence; a [[deletion|deletion]] removes one or more. Unlike a substitution, which keeps the total length the same, these change how many letters there are — and that is exactly why they can be so disruptive. The reason is the [[reading-frame|reading frame]].

The ribosome reads codons three letters at a time, starting from a fixed point and never pausing to recount. It simply takes the next three, then the next three. If you insert or delete a number of bases that is not a multiple of three, every codon after that point shifts. This is a [[frameshift-mutation|frameshift mutation]].

Seeing the frame shift

Wild type   THE BIG RED CAT ATE THE RAT
            (read in 3-letter words from the left)

1-base insertion of 'X' near the start:
            THE BXI GRE DCA TAT ETH ERA T..
            -> every word after the insert is garbage
            -> a STOP codon usually appears soon -> truncated protein

1-base deletion (remove the 'B'):
            THE IGR EDC ATA TET HER AT.
            -> same disaster: the frame is shifted by one

3-base deletion (remove 'RED', a whole word):
            THE BIG CAT ATE THE RAT
            -> frame preserved! one word lost, the rest reads fine

Using English words as codons: shifting by one wrecks everything downstream; removing a multiple of three keeps the frame.

Why frameshifts hit so hard

After a frameshift, the amino-acid sequence becomes meaningless and a [[gen-stop-codon|stop codon]] soon appears by chance in the new frame. The protein ends early and is usually non-functional — a classic [[loss-of-function|loss-of-function]] mutation. Many deletions in the dystrophin gene work this way: Duchenne muscular dystrophy is largely caused by frame-shifting deletions, while in-frame deletions of the same gene tend to cause a milder form.