Nonsynonymous substitution

A nonsynonymous substitution is a point mutation in a protein-coding gene that changes the amino acid sequence of the resulting protein. Because it alters the biochemical properties of the gene product, nonsynonymous mutations are typically subject to strong purifying selection — most are deleterious and rapidly removed from populations. The rate of nonsynonymous substitution relative to synonymous substitution (dN/dS) is the primary molecular signature used to detect selective constraint and positive selection in comparative genomics.

The probability that a nonsynonymous mutation is beneficial is extremely low. Most proteins have been optimized by billions of years of evolution, and random changes to their structure are more likely to disrupt function than to improve it. This is why the genome-wide dN/dS ratio is typically far below 1: purifying selection dominates molecular evolution.

Nonsynonymous substitution is the molecular record of evolution's editing process. Most entries are deletions.