Nonsynonymous Synonymous Variants Demand for a Paradigm Shift in Genetics

Abstract

Synonymous (also known as silent) variations are by definition not considered to change the coded protein. Still many variations in this category affect either protein abundance or properties. As this situation is confusing, we have recently introduced systematics for synonymous variations and those that may on the surface look like synonymous, but these may affect the coded protein in various ways. A new category, unsense variation, was introduced to describe variants that do not introduce a stop codon into the variation site, but which lead to different types of changes in the coded protein. Many of these variations lead to mRNA degradation and missing protein. Here, consequences of the systematics are discussed from the perspectives of variation annotation and interpretation, evolutionary calculations, nonsynonymous-to-synonymous substitution rates, phylogenetics and other evolutionary inferences that are based on the principle of (nearly) neutral synonymous variations. It may be necessary to reassess published results. Further, databases for synonymous variations and prediction methods for such variations should consider unsense variations. Thus, there is a need to evaluate and reflect principles of numerous aspects in genetics, ranging from variation naming and classification to evolutionary calculations.

Keywords: Synonymous variation; distribution of fitness effects; nonsynonymous-to-synonymous substitution ratio; phylogenetics; silent variation; unsense variation.

Fig. (1)

Classification of synonymous (red) and unsense (blue) variants and their consequences at DNA (center), RNA (middle), and protein (outer circle) levels. The inner circle indicates DNA variants, which although synonymous can affect transcription factor (TF) binding, and thereby protein production. The middle circle depicts mRNA level alterations, and on the outer ring are shown the protein level effects. At mRNA, synonymous variants are either true synonymous or those that affect RNA structure and stability. Synonymous variants at the protein level have either native or misfolded structure or affect protein activity. Changes to protein abundance are common. PTM indicates post-translational protein modification. The three categories of unsense variants (blue) affect aberrant splicing, splicing regulation, or miRNA binding. Many of these variants have an effect on protein abundance, and often there is no protein at all. Aberrant splicing and splicing regulation affecting variants can lead also to protein insertion or deletion, if the variant position is close to the C-terminus or the mRNA is not degraded by nonsense-mediated decay.