Pervasive Strong Selection at the Level of Codon Usage Bias in Drosophila melanogaster

Abstract

Codon usage bias (CUB), where certain codons are used more frequently than expected by chance, is a ubiquitous phenomenon and occurs across the tree of life. The dominant paradigm is that the proportion of preferred codons is set by weak selection. While experimental changes in codon usage have at times shown large phenotypic effects in contrast to this paradigm, genome-wide population genetic estimates have supported the weak selection model. Here we use deep genomic population sequencing of two Drosophila melanogaster populations to measure selection on synonymous sites in a way that allowed us to estimate the prevalence of both weak and strong purifying selection. We find that selection in favor of preferred codons ranges from weak (|Nes| ∼ 1) to strong (|Nes| > 10), with strong selection acting on 10–20% of synonymous sites in preferred codons. While previous studies indicated that selection at synonymous sites could be strong, this is the first study to detect and quantify strong selection specifically at the level of CUB. Further, we find that CUB-associated polymorphism accounts for the majority of strong selection on synonymous sites, with secondary contributions of splicing (selection on alternatively spliced genes, splice junctions, and spliceosome-bound sites) and transcription factor binding. Our findings support a new model of CUB and indicate that the functional importance of CUB, as well as synonymous sites in general, have been underestimated.

Conserved codon adaptation in highly expressed genes is associated with higher regularity in mRNA secondary structures

“…Genome-wide codon bias is driven by weak selective forces, mutation and genetic drift (6). While selection has been demonstrated to play a dominant role of in non-mammalian species (36,51), in mammalian species mutational biases are more prominent (52,53) and the contribution of selection is more disputed (6,22). This correlates well with our findings where the conserved bias in codon use and mRNA secondary structures in M. musculus is less pronounced than in the other four model species.…”

Is adaptation limited by mutation? A timescale-dependent effect of genetic diversity on the adaptive substitution rate in animals

“…Our results may also be influenced by differences between groups in terms of selection on codon usage. It has been shown that in Drosophila synonymous mutations are subject to both weak and strong selection [47,48], which in turn has been shown to potentially lead to an upward bias in the estimation of α [49] (at least when α is estimated as 1…”

Quantifying shifts in natural selection on codon usage between protein regions: A population genetics approach

“…CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted December 20, 2020. ; https://doi.org/10.1101/2020.12.18.423529 doi: bioRxiv preprint Shah and Gilchrist, 2011;Gilchrist et al, 2015;Landerer et al, 2020;Lawrie et al, 2013;Machado et al, 2020). One particularly powerful population genetics approach is the Ribosomal Overhead Cost Stochastic Evolutionary Model of Protein Production Rates (ROC-SEMPPR), which is able to separate out the effects of mutation and selection on codon usage by accounting for the natural variation in intergenic gene expression (Shah and Gilchrist, 2011;Gilchrist et al, 2015;Wallace et al, 2013).…”