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Molecular evolution is inherited change in molecules such as DNA and proteins across generations. Mutations introduce new variants; natural selection and genetic drift influence which variants persist. Comparing a nucleotide sequence or protein sequence between lineages therefore supplies evidence about their history as well as their present chemistry.

An important early example was the comparison of cytochrome c from different organisms. Emanuel Margoliash's 1963 report connected differences in protein primary structure to evolutionary relationships. The experimental input was the ordered amino acid residues of the proteins, rather than only their bulk composition or their shared function. Placing corresponding positions side by side made molecular differences countable.^[ref]

For a deliberately simplified example, suppose two already aligned sequences have $k=8$ differing positions among $n=100$ compared positions. Their observed difference fraction is $k/n=0.08$. That statistic is not itself a divergence time. If both lineages split $t$ time units ago and each accumulates substitutions at the same constant rate $r$ per position per unit time, their expected accumulated pairwise molecular divergence isThe factor two counts the two descendant branches. At low divergence, the observed difference fraction can approximate $d$; repeated changes at one position can conceal earlier changes, and unequal branch rates invalidate the equal-rate simplification. A molecular clock additionally needs a rate or time calibration to turn molecular differences into dates.

Sequence identity is a measured agreement between aligned positions. homology is a historical relationship of common descent; it is not a percentage. Orthology and paralogy further distinguish relationships associated with lineage splitting and gene duplication. These distinctions matter when a phylogenetic tree is inferred from a chosen gene rather than directly observed.

The neutral theory of molecular evolution provides a complementary population-level explanation: molecular change need not always be an adaptive improvement. Motoo Kimura's 1968 argument emphasized the potential importance of neutral changes and genetic drift, while leaving room for natural selection.^[ref]

Motoo Kimura developed mathematical approaches to population genetics and the neutral theory of molecular evolution. His 1968 paper argued that observed molecular substitution rates would be difficult to explain if every substitution represented favorable natural selection. Many changes could instead have little effect on biological fitness and spread through genetic drift.^[ref]

A simple neutral calculation makes the idea concrete. In a diploid biological population of $N$ individuals, $2N\mu$ neutral copies arise per generation when the mutation rate is $\mu$, and each has fixation probability $1/(2N)$. Their product is $\mu$: under these assumptions, the substitution rate equals the neutral mutation rate. This distinguishes molecular change from inevitable adaptive improvement.

Neutral evolution is change in inherited variants whose differences do not affect biological fitness in the population and environment being modeled. Their allele frequencies can change through genetic drift even without a selective advantage. Neutrality concerns effects on reproductive success, rather than requiring that the underlying DNA sequences are chemically identical.

An idealized diploid population with $N$ individuals makes a useful prediction. If the neutral mutation rate per copy per generation is $\mu$, the expected value of the number of new copies is $2N\mu$. Each has fixation probability $1/(2N)$, so the neutral substitution rate isThe cancellation explains why a molecular clock can reflect a mutation rate rather than population size under these assumptions. Motoo Kimura's molecular argument motivated a major role for neutral evolution; it does not assert that every mutation is neutral.^[ref]

The neutral theory of molecular evolution proposes that much molecular evolutionary change arises from mutations with little or no effect on biological fitness, whose fates are governed largely by genetic drift. It concerns molecular substitutions and variation; it does not require adaptive traits or natural selection to be absent. Motoo Kimura argued in 1968 that observed molecular substitution rates were difficult to explain if all such changes were advantageous.^[ref]

The basic neutral calculation is especially revealing. In an idealized diploid biological population of size $N$, a neutral mutation rate $\mu$ per gene copy produces $2N\mu$ new copies per generation. Each has fixation probability $1/(2N)$, so the substitution rate isMore new mutations in a larger population are offset by the lower fixation chance of each one. This is a model prediction with explicit neutrality and population assumptions, not a claim that every mutation is neutral.