The Standard Genetic Code Facilitates Exploration of the Space of Functional Nucleotide Sequences

Abstract

The standard genetic code is well known to be optimized for minimizing the phenotypic effects of single-nucleotide substitutions, a property that was likely selected for during the emergence of a universal code. Given the fitness advantage afforded by high standing genetic diversity in a population in a dynamic environment, it is possible that selection to explore a large fraction of the space of functional proteins also occurred. To determine whether selection for such a property played a role during the emergence of the nearly universal standard genetic code, we investigated the number of functional variants of the Escherichia coli PhoQ protein explored at different time scales under translation using different genetic codes. We found that the standard genetic code is highly optimal for exploring a large fraction of the space of functional PhoQ variants at intermediate time scales as compared to random codes. Environmental changes, in response to which genetic diversity in a population provides a fitness advantage, are likely to have occurred at these intermediate time scales. Our results indicate that the ability of the standard code to explore a large fraction of the space of functional sequence variants arises from a balance between robustness and flexibility and is largely independent of the property of the standard code to minimize the phenotypic effects of mutations. We propose that selection to explore a large fraction of the functional sequence space while minimizing the phenotypic effects of mutations contributed toward the emergence of the standard code as the universal genetic code.

Frameshifting preserves key physicochemical properties of proteins

“…In this sense, our results capture the most extreme case (i.e., frameshifts of full-length proteins): Hybrid proteins are expected to be even more similar in physicochemical properties to their wild-type counterparts. Recently, Tripathi and Deem (35) provided evidence suggesting that the retention of physicochemical properties of amino acids upon point mutations improves the exploration of functional nucleotide sequences at intermediate evolutionary time scales. We predict that this may also apply to the much more impactful, sequence-altering instances of frameshifting mutations.…”

Invariants of Frameshifted Variants

“…the full-length frameshifts, while realistic frameshift events over shorter stretches are expected to show even higher levels of profile similarity between wildtype proteins and their locally frameshifted variants. Recently, Tripathi and Deem (39) provided evidence suggesting that the retention of physicochemical properties of amino acids upon point mutations, a known feature of the universal genetic code, improves the exploration of functional nucleotide sequences at intermediate evolutionary time scales. Our prediction is that similar conclusion applies not only to single-nucleotide substitutions, as explored by these authors, but also to the much more impactful, sequence-altering instances of both local and global frameshifting mutations.…”

Little evidence the standard genetic code is optimized for resource conservation

“…In contrast, a method known as amino acid permutation generates alternative codes by randomly permuting the twenty standard amino acids amongst the synonymous codon blocks (Haig and Hurst 1991). This method, which is most commonly used in the field (Haig and Hurst 1991; Ardell 1998; Freeland and Hurst 1998; Freeland et al 2000; Gilis et al 2001; Archetti 2004; Caporaso et al 2005; Goodarzi et al 2005a; Goodarzi et al 2005b; Novozhilov et al 2007; Butler et al 2009; Tripathi and Deem 2018), generates alternative codes that preserve a different key property of the SGC, namely the structure of the synonymous codons blocks. Importantly, in these alternative codes, the number of codons per amino acid can change drastically relative to the SGC, because the permutation of amino acids amongst the synonymous blocks is random.…”