Read between the Lines: Diversity of Nontranslational Selection Pressures on Local Codon Usage

Abstract

Protein coding genes can contain specific motifs within their nucleotide sequence that function as a signal for various biological pathways. The presence of such sequence motifs within a gene can have beneficial or detrimental effects on the phenotype and fitness of an organism, and this can lead to the enrichment or avoidance of this sequence motif. The degeneracy of the genetic code allows for the existence of alternative synonymous sequences that exclude or include these motifs, while keeping the encoded amino acid sequence intact. This implies that locally, there can be a selective pressure for preferentially using a codon over its synonymous alternative in order to avoid or enrich a specific sequence motif. This selective pressure could –in addition to mutation, drift and selection for translation efficiency and accuracy– contribute to shape the codon usage bias. In this review, we discuss patterns of avoidance of (or enrichment for) the various biological signals contained in specific nucleotide sequence motifs: transcription and translation initiation and termination signals, mRNA maturation signals, and antiviral immune system targets. Experimental data on the phenotypic or fitness effects of synonymous mutations in these sequence motifs confirm that they can be targets of local selection pressures on codon usage. We also formulate the hypothesis that transposable elements could have a similar impact on codon usage through their preferred integration sequences. Overall, selection on codon usage appears to be a combination of a global selection pressure imposed by the translation machinery, and a patchwork of local selection pressures related to biological signals contained in specific sequence motifs.

Exonic splicing code and protein binding sites for calcium

“…Apart from global synonymous codon selection pressures such as GC content, secondary structure, mutation and drift, ESEs/ESSs, translation efficiency, sense-to-nonsense codon susceptibility and cellular differentiation, potential local factors cannot be excluded ( 115 ), including those related to Ca 2+ binding. Ca 2+ ions are initially bound by EF-hand ligands in the more flexible N-terminal part of the loop (positions 1, 3, 5 and 7, Figure 1A ) whereas C-terminal ligands, particularly position 12, are too distant to chelate directly (reviewed in 52).…”

Subfunctionalisation of paralogous genes and evolution of differential codon usage preferences: the showcase of polypyrimidine tract binding proteins

“…The non equal use of synonymous codons has puzzled biologists since it was first described. It has given rise to fruitful (and unfruitful) controversies between defenders of all-is-neutralism and defenders of all-is-selectionism , and has launched further the quest for additional molecular signaling beyond codons themselves (Callens et al, 2021). The main questions around CUPrefs are twofold.…”

Transcriptomic, proteomic and functional consequences of codon usage bias in human cells during heterologous gene expression

“…A reduced single nucleotide polymorphism density and a decreased rate of synonymous substitutions have further been reported in these regulatory regions, which can be interpreted as a signature for selective pressure 79,80 . Thus, selection against mRNA mis-processing can constitute an important selective force that results in concomitant selection for a precise local CUBias 81 . This selective force has even been proposed to outperform translational selection in Drosophila melanogaster 82 .…”