Mosaic translation hypothesis: chimeric polypeptides produced via multiple ribosomal frameshifting as a basis for adaptability

Abstract

How many different proteins can be produced from a single spliced transcript? Genome annotation projects overlook the coding potential of reading frames other than that of the reference open reading frames (refORFs). Recently, alternative open reading frames (altORFs) and their translational products, alternative proteins, have been shown to carry out important functions in various organisms. AltORFs overlapping refORFs or other altORFs in a different reading frame may be involved in one fundamental mechanism so far overlooked. A few years ago, it was proposed that altORFs may act as building blocks for chimeric (mosaic) polypeptides, which are produced via multiple ribosomal frameshifting events from a single mature transcript. We adopt terminology from that earlier discussion and call this mechanism mosaic translation. This way of extracting and combining genetic information may significantly increase proteome diversity. Thus, we hypothesize that this mechanism may have contributed to the flexibility and adaptability of organisms to a variety of environmental conditions. Specialized ribosomes acting as sensors probably played a central role in this process. Importantly, mosaic translation may be the main source of protein diversity in genomes that lack alternative splicing. The idea of mosaic translation is a testable hypothesis, although its direct demonstration is challenging. Should mosaic translation occur, we would currently highly underestimate the complexity of translation mechanisms and thus the proteome.

Why is the average collateral effect of synonymous mutations so similar across alternative reading frames?

“…After some time this would leave essentially no trace of the original gene, and may explain the origin of some “orphan genes” - but to our knowledge no specific examples of this have yet been demonstrated. In eukaryotes, a related mechanism termed “mosaic translation” has been hypothesised but not demonstrated (Çakır et al 2021) - this is where different parts of a spliced RNA transcript are read in different reading frames, producing “mosaic” proteins. The second process of remodelling has recently been demonstrated to play a non-trivial role in gene origins in E. coli .…”