The concept that during evolution the number of nonadaptive, or ‘neutral’, substitutions in the nucleotides of nucleic acids (DNA or RNA), and hence in the proteins encoded by the nucleic acids, is proportional to time. Hence, by comparing the DNA or proteins of species that diverged a known length of time ago (e.g. determined from fossil evidence), it is possible to calculate the average substitution rate, thereby calibrating the ‘molecular clock’. Comparative studies of different proteins in various groups of organisms tend to show that the number of neutral substitutions per site per year is fairly consistent over time, especially if many genes are considered to average out fluctuations in evolutionary rate due to natural selection. Hence, given a fairly constant rate of molecular evolution in comparable sequences of macromolecules, it is possible to date evolutionary events that occurred before any corroborative fossil record. See neutral theory of molecular evolution.