Massive loss of transcription factors and the initial diversification of placental mammals

As one of the most successful categories of organisms, mammals occupy a variety of niches on earth as a result of macroevolution. Transcription factors (TFs), the basic regulators of gene expression, may also evolve during mammalian phenotypic diversification and macroevolution. To examine the relationship between TFs and mammalian macroevolution, we analyzed 140,821 de novo-identified TFs and their birth and death histories from 96 mammalian species. Gene tree vs. species tree reconciliation revealed that mammals experienced an upsurge in TF losses around 100 million years ago and also near the K-Pg boundary, thus implying a relationship with the divergence of placental animals. From approximately 100 million years ago to the present, losses dominated TF events without a significant change in TF gains. To quantify the effects of this TF pruning on mammalian macroevolution, we analyzed rates of molecular evolution and expression profiles of regulated target genes. Surprisingly, TF loss decelerated, rather than accelerated, molecular evolutionary rates of their target genes, suggesting increased functional constraints. Furthermore, an association study revealed that massive TF losses are significantly positively correlated with solitary behavior, nocturnality, reproductive-seasonality and insectivory life history traits, possibly through rewiring of regulatory networks.