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

Abstract

The standard genetic code has been shown to have multiple interesting properties which impact on molecular biology and the evolutionary process. One facet of molecular biology where code structure is particularly important is the origin and evolution of overlapping genes. We have previously reported that the structure of the standard genetic code ensures that synonymous mutations in a protein coding gene will lead to a remarkably similar average "collateral" mutation effect size in at least four out of the five alternative reading frames. Here we show that only 0.26% of alternative codes with the block structure of the standard genetic code perform at least as well as the standard code in this property. Considering this finding within a code optimality framework suggests that this consistent effect size across the different frames may be adaptive. Here we give context for this finding and present a simple model where a trade-off between evolvability and robustness leads to an average mutation effect size which maximises population fitness. This supports the intuition that similar mutation effects across the different alternative reading frames may be an adaptive property of the standard genetic code which facilitates evolvability through the use of alternative reading frames.

Alternative reading frames are an underappreciated source of protein sequence novelty

“…It has similarly been suggested that there is a tendency for secondary structures found in the sense strand to be retained in antisense, in terms of the types of amino acids encoded (Zull and Smith 1990) and a tendency for conservative mutations in one strand to also be conservative in the other (Konecny et al 1993). This study of conservation in antisense has recently been extended to other frames, finding remarkable similarity across frames (Wichmann andArdern 2019, 2022).…”

“…Even synonymous mutations in a coding sequence in effect explore sequence space in alternative frames. The surprising similarity in this "collateral" effect size across alternative frames (Wichmann and Ardern 2019) may facilitate evolutionary exploration (Wichmann and Ardern 2022).…”