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A phylogenetic analysis of DNA sequences from the C3/C4/C5 complement-component family of vertebrates supported the hypothesis that the C5 gene diverged first from the common ancestor of C3 and C4 and that C3 and C4 diverged later. The close relationship of C3 and C4 was further supported by the fact that a hagfish complement-component gene showed evidence of being more closely related to both C3 and C4 than to C5. This phylogeny is most consistent with the hypothesis that the alternative complement pathway was the first to evolve, followed by the terminal pathway and then by the classical pathway.

Phylogeny of the C3/C4/C5 complement-component gene family indicates that C5 diverged first.