Abstract
Synonymous sites are generally assumed to be subject to weak selective constraint. For this reason, they are often neglected as a possible source of important functional variation. We use site frequency spectra from deep population sequencing data to show that, contrary to this expectation, 22% of four-fold synonymous (4D) sites in Drosophila melanogaster evolve under very strong selective constraint while few, if any, appear to be under weak constraint. Linking polymorphism with divergence data, we further find that the fraction of synonymous sites exposed to strong purifying selection is higher for those positions that show slower evolution on the Drosophila phylogeny. The function underlying the inferred strong constraint appears to be separate from splicing enhancers, nucleosome positioning, and the translational optimization generating canonical codon bias. The fraction of synonymous sites under strong constraint within a gene correlates well with gene expression, particularly in the mid-late embryo, pupae, and adult developmental stages. Genes enriched in strongly constrained synonymous sites tend to be particularly functionally important and are often involved in key developmental pathways. Given that the observed widespread constraint acting on synonymous sites is likely not limited to Drosophila, the role of synonymous sites in genetic disease and adaptation should be reevaluated.
Highlights
As there are 64 codons and only 20 amino acids, most amino acids can be encoded by more than a single codon
For our collection of synonymous sites, to prevent any confusion of synonymous vs. non-synonymous selection acting on a given codon position, we focused on the third codon positions of the four-fold degenerate amino acids (Proline, Alanine, Threonine, Glycine, and Valine)
The strong constraint at synonymous sites in D. melanogaster measured in this paper represents a powerful force
Summary
As there are 64 codons and only 20 amino acids, most amino acids can be encoded by more than a single codon. Expressed genes and codons encoding functionally important amino acids generally display biased patterns of codon usage [9,10,11]. This observation led to the theory that selection for translation optimization generates higher levels of codon bias [12,13,14,15]. It is thought that the speed and accuracy of mRNA translation is higher for a subset of codons, referred to as ‘‘optimal’’ (‘‘preferred’’) codons [14,15,16,17,18,19] Such codons are translated more accurately and more efficiently because they are recognized by more abundant tRNA molecules with more specific anti-codon binding [14,20,21]. If synonymous sites harbor highly deleterious variants under strong purifying selection, that must change our view of the functional importance of synonymous sites and their potential role in genetic disease, as a possible source for adaptation, and as the neutral foil in tests for selection
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