Nonsynonymous Synonymous Variants Demand for a Paradigm Shift in Genetics

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.