Wobble Hypothesis

Abstract

The original wobble hypothesis with its extended codon–anticodon base pairs played a crucial role in understanding the working of the messenger RNA (mRNA) translation machinery. Wobble pairing reduces the number of transfer RNAs (tRNAs) needed for mRNA translation, but also tends to reduce translation efficiency and accuracy. Many nucleotide modifications have been discovered that either increase or decrease the wobble versatility of nucleotides, leading to increased decoding capacity without serious reduction in translation efficiency and accuracy. Recent studies on tRNA have led to the expanded wobble hypothesis that extends the wobble hypothesis by invoking wobble pairing between the third anticodon site (NIII) and the first codon site (N1), conditional on a CII/G2 or GII/C2 with three hydrogen bonds. This hypothesis implies that the anticodon UCG would wobble pair with stop codon UGA through a wobble UIII/G1 pair, and should therefore be strongly selected against. The hypothesis explains not only the avoidance of tRNAArg/UCG in diverse evolutionary lineages, but in particular why tRNAArg/UCG should be avoided in most eubacterial species and ancestral mitochondrial lineages where UGA is used as a stop codon, and why it is present in derived mitochondrial lineages such as vertebrate mitochondrial genomes, where UGA is no longer used as a stop codon. Wobble pairing implies the theoretical possibility of adding new base pairs of novel nucleotides to protein-coding genes to increase the coding capacity.