Duplication-Divergence Model of PPI Evolution. Simplified gene tree illustrating the emergence of new PPIs under the duplication-divergence model of PPI evolution. In an ancestral species, the gene encoding a self-interacting protein, A, is duplicated. From the resulting genes A1 and A2, A1 at some point loses its capability for self-interaction. Subsequent speciation forms the rat (R) and mouse (M) lineages, which evolve differently: in the mouse lineage, gene M1 is duplicated again, in the rat lineage R2 is duplicated. One of the R2 duplicates loses its capability for homodimerization due to deleterious mutations. Colors indicate the two groups of orthologous genes. Note that all depicted PPIs are homologous in the narrow sense of the word, because they share a common ancestor.