Fig. 7.

Schematic representation of evolutionary events in the NAD biosynthesis pathway. The scheme illustrates major evolutionary events in Metazoa detected in our phylogenetic analyses of NAD metabolism. The time of occurrence of human-like NMNAT1 and NMNAT3 has been reported previously (61), and it has been identified that human-like NMNAT2 most likely originated in the last common ancestor (LCA) of vertebrates, while human-like NMNAT1/3 can be traced back to the LCA of Placentalia (SI Appendix, Fig. S9). To test whether the rise of human-like NMNAT1/3 was associated with an event of rapid sequence diversification in NNMT, we conducted a test of positive selection specific to the branch leading to the LCA of Placentalia using a coding DNA substitution rate ratio model. Indeed, we obtain a strong signature of positive selection for NNMT in the tested branch and can pinpoint residue 171 as being significantly associated with the signature of positive selection (SI Appendix, Figs. S7 and S8). Specific events in the evolution of NMNATs coincide with those of NamPT or NNMT, indicating a coevolution of functions beyond those identified in the present study. The tree is a schematic representation of selected taxa and is based on information provided by the Tree of Life Web Project (80).