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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]

A tetrapod limb is a paired appendage of a tetrapod, such as a forelimb or hindlimb, organized around a shared inherited skeletal pattern. In a familiar forelimb, one proximal bone, the humerus, is followed by the radius bone and ulna, then more distal elements and limb digits. The corresponding structures can differ greatly in proportions and use. Comparing their relationships, rather than just their overall shape, is central to recognizing homology.

The transition from a fin to a limb was not an instantaneous appearance of an entire new skeleton. A 2006 study of Tiktaalik described a pectoral fin with an expanded distal internal skeleton and articulations permitting a substrate-supported posture. The reconstructed joint configurations included flexed shoulder and elbow regions and an extended distal region. This indicates precursors of limb-like support in a finned animal; it does not make every distal fin element a limb digit.^[ref]

A useful comparison traces the humerus, radius bone and ulna in two differently shaped forelimbs, then asks which elements contact one another. A wing and a walking appendage can preserve corresponding elements while redistributing their lengths and mechanical roles. Shared ancestry and present function are related questions, but one cannot be read directly from the other.