Synonymous codon bias and functional constraint on GC3-related DNA backbone dynamics in the prokaryotic nucleoid.

Gregory A Babbitt,André O Hudson,Mohammed A Alawad,Katharina V Schulze

doi:10.1093/nar/gku811

Gregory A Babbitt, André O Hudson + Show 2 more

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https://doi.org/10.1093/nar/gku811

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Abstract

While mRNA stability has been demonstrated to control rates of translation, generating both global and local synonymous codon biases in many unicellular organisms, this explanation cannot adequately explain why codon bias strongly tracks neighboring intergene GC content; suggesting that structural dynamics of DNA might also influence codon choice. Because minor groove width is highly governed by 3-base periodicity in GC, the existence of triplet-based codons might imply a functional role for the optimization of local DNA molecular dynamics via GC content at synonymous sites (≈GC3). We confirm a strong association between GC3-related intrinsic DNA flexibility and codon bias across 24 different prokaryotic multiple whole-genome alignments. We develop a novel test of natural selection targeting synonymous sites and demonstrate that GC3-related DNA backbone dynamics have been subject to moderate selective pressure, perhaps contributing to our observation that many genes possess extreme DNA backbone dynamics for their given protein space. This dual function of codons may impose universal functional constraints affecting the evolution of synonymous and non-synonymous sites. We propose that synonymous sites may have evolved as an ‘accessory’ during an early expansion of a primordial genetic code, allowing for multiplexed protein coding and structural dynamic information within the same molecular context.

Highlights

The nature of codon usage bias and its relation to natural selection acting at synonymous sites is a long-standing problem in molecular evolutionary theory [1,2]
We investigated the DNA flexibility allowable via synonymous codon bias in a single-gene context (L,L-diaminopimelate aminotransferase or dapL) across a vastly divergent taxa. dapL is a key enzyme involved in the synthesis of intermediates that are necessary for peptidoglycan and lysine synthesis [46]
Across all prokaryotic species clades in our analysis, we report strong and significant overall linear trends associating the levels of codon bias and the intrinsic DNA flexibility averaged over whole genomes

Summary

Introduction

The nature of codon usage bias and its relation to natural selection acting at synonymous sites is a long-standing problem in molecular evolutionary theory [1,2]. Early observations of universal evolutionary changes to GC content [6] and a strong association between preferred synonymous codons and their relative representation in the t-RNA pool [7,8] has long suggested that completely neutrally evolving base substitutions may exist only in theory, rather than fact. While there is good evidence in many microbes for selection acting on the efficiency/accuracy of translation, there is still no explanation as to why codon bias so strongly tracks the local intergenic GC content in the genomes of most other organisms [14,15]; especially as it is hard to imagine how molecular evolution in the intergenic regions can affect the molecular events on the ribosome. A process limited to sexually recombining genomes, has been previously invoked as an explanation [16], it is not a universal ex-

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