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Emanuel Margoliash was a biochemist whose work on cytochrome c connected protein primary structure, molecular function and evolution. He isolated and sequenced the protein from different organisms and helped develop comparisons of amino acid sequences as evidence for phylogenetic trees.^[ref]

His 1963 paper, Primary structure and evolution of cytochrome c by Emanuel Margoliash, made the structural comparison itself a source of evolutionary evidence. Subsequent collaborative work assembled a tree from twenty cytochrome-c sequences, combining published sequences with measurements from his laboratory.^[ref]

A toy example shows the measurable idea. Align the five-residue strings ACGKT and ACGRT: four positions agree and one differs, giving an observed mismatch fraction $1/5=0.2$. These are invented strings, not Margoliash's data. An observed mismatch count is not automatically elapsed evolutionary time: repeated substitutions can hide earlier changes. The power of the approach is to make molecular resemblance explicit and test competing explanations, while retaining the distinction between sequence observations and an inferred history.

Indrani Mukharji is the author of a 2020 scientific memoir of Emanuel Margoliash. The memoir explains how work on cytochrome c connected protein chemistry with the reconstruction of evolutionary relationships. It follows the isolation and sequencing of the protein through to comparisons between species, showing how a laboratory material became evidence for evolution.^[ref]

One concrete example is the assembly of a phylogenetic tree from cytochrome c sequences for 20 species. The useful idea is to compare corresponding positions in the same protein, rather than treat every difference between organisms as an unrelated observation. Indrani Mukharji's contribution here is documenting and explaining that scientific history; authorship of the memoir is distinct from authorship of the earlier experiments it describes.^[ref]

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]