gene is inactivated in mammalian lineages that lack enamel or teeth.

Loss of tooth or enamel is widespread in multiple mammal lineages. Although several studies have been reported, the evolutionary mechanisms of tooth/enamel loss are still unclear. Most previous studies have found that some tooth-related genes have been inactivated in toothless and/or enamel-less mammals, such as , , , , , , etc. Here, we conducted evolutionary analyses on playing a key role in amelogenesis, to interrogate the mechanisms. We obtained the sequences from 116 species, including edentulous and enamel-less mammals. The results shows that variant ORF-disrupting mutations were detected in coding region among nine edentulous baleen whales and three enamel-less taxa (pygmy sperm whale, aardvark, nine-banded armadillo). Furtherly, selective pressure uncovered that the selective constraints have been relaxed among all toothless and enamel-less lineages. Moreover, our results support the hypothesis that mineralized teeth were lost or degenerated in the common ancestor of crown Mysticeti through two shared single-base sites deletion in exon 4 and 5 of among all living baleen whales. / values on transitional branches were used to estimate inactivation records. In the case of aardvark, inactivation of was estimated at 23.60-28.32 Ma, which is earlier than oldest aardvark fossil record (, ~19 Ma), suggesting that inactivation may result in degeneration or loss of enamel. Conversely, the inactivation time of estimated in armadillo (10.18-11.30 Ma) is later than oldest fossil record, suggesting that inactivation of may result from degeneration or loss of enamel in these mammals. Our findings suggested that different mechanisms of degeneration of tooth/enamel might exist among toothless and enamel-less lineages during evolution. Our study further considered that is a novel gene for studying tooth evolution.