Ribosome decoding memory directs translational re-coding of codon repeats

Long runs of consecutive codons are generally thought to impede elongation by depleting cognate tRNAs. However, in Huntington’s disease, ribosomes translate hundreds of consecutive CAG codons without catastrophic stalling.

Here, we systematically profile ribosome behavior across repeats of all 20 amino acids encoded in the human genome. For proline and lysine repeats – commonly considered difficult to decode – we find that ribosomes accelerate after an initial phase of slow decoding, a phenomenon we term adaptive decoding. Remarkably, codon-specific decoding memory enables iterative translation of arginine repeats, generating internally expanded protein products.