Most functional domains in Hippo genes are under purifying selection and have coevolved with other functional domains. (ABCD) are Drosophila Hippo, Warts, Mats and Dachs, with the number of amino acids marked below. Red, blue and green bars indicate sites under purifying selection, neutral evolution and positive selection, and black frames indicate identified functional domains. In (D) the symbol * indicates the “unique insert in myosin head domain” and the big frame from 274 aa to 1025 aa indicates “myosin head domain”. In (EFGH) red dots indicate coevolved sites in two genes. (E) Hippo’s 20–300 aa coevolve with Warts’s 600–900 aa (marked by the dashed black box); these two regions correspond to Hippo’s protein kinase domain and Warts’s protein kinase domain. Hippo’s 440–470 aa coevolve with Warts’s 600–900 aa; the former does not correspond to any identified domain in Hippo but the latter corresponds to the protein kinase domain. Also, Hippo’s 580–650 aa coevolve with Warts’s 640–1100 aa; these two regions largely correspond to Hippo’s Sarah domain and Warts’s AGC-kinase C-terminal domain. (F) Hippo’s 20–300 aa coevolve with the whole Mats (marked by the dashed black box), indicating that the whole Mats may be under purifying selection. (G) While coevolution signals occur evenly in the whole Mats, they exist only in Warts’s 700–1000 aa. This region in Warts corresponds to its protein kinase domain, which is under purifying selection. (H) Sites under purifying selection in Dachs (the coiled-coil domain, the myosin head domain, and the tail domain) coevolve with sites under purifying selection in Warts (the protein kinase domain). Notably, Dachs’s tail domain is under strong purifying selection and coevolves with Warts’s protein kinase domain (marked by the black boxes).