The theory, originally proposed in the late 1960s by Motoo Kimura (1924–94) and others, that most evolutionary changes at the molecular level are due to the random process of genetic drift acting on mutations, rather than natural selection. Its proponents, while recognizing the importance of selection in determining functionally significant traits, hold that the great majority of the differences in macromolecular structures observed between individuals in a population are of no adaptive significance and have no impact on the reproductive success of the individual in which they arise. Hence, frequencies of the corresponding mutant alleles are governed by purely random events. This contrasts with the orthodox neo-Darwinian view that nearly all evolutionary changes have adaptive value for the organism and arise through natural selection. For example, many enzymes exhibit polymorphism with regard to their amino acid sequence, giving rise to morphological variants that are detectable by electrophoresis. However, these variants may apparently perform equally well, and ‘neutralists’ would argue that evolution consists essentially of random shuffling between them. ‘Selectionists’ retort that such variants are likely to have subtle differences in function and are susceptible to selective forces, such as minor environmental changes. However, the accumulated sequence data for genomes and proteins largely support the neutral theory. The observed differences in base sequence between species are generally much greater for introns (noncoding sequences) and pseudogenes (nonfunctional or ‘dead’ genes), and for synonymous base substitutions (i.e. ones that do not change the amino acid in the resulting protein) than they are at sites that are critical for gene function or for nonsynonymous substitutions (i.e. ones that alter the corresponding amino acid and thereby affect the properties of the resulting protein). Because neutral mutations arise on average at a fairly constant rate, they are often used as the basis of a molecular clock to estimate the time elapsed since the divergence of species.