The insulin/insulin-like signaling and target of rapamycin (IIS/TOR) network regulates lifespan and reproduction, as well as metabolic diseases, cancer, and aging. Despite its vital role in health, comparative analyses of IIS/TOR have been limited to invertebrates and mammals. An international team led by Dr. Tonia S. Schwartz, postdoctoral fellow in the office of energetics at the University of Alabama at Birmingham; Dr. Suzanne McGaugh of the University of Minnesota; and Dr. Anne M. Bronikowski of Iowa State University, recently conducted an extensive evolutionary analysis of the IIS/TOR network across 66 amniotes (reptiles and mammals). Reptiles are most closely related to mammals but can differ dramatically in metabolic processes and how they age and reproduce. Comparing the genetics and physiology between reptiles and mammals can aid in understanding the genetic basis for these traits.
The team found some of the critical IIS/TOR genes that cause cancer, alter reproduction, and regulate lifespan in laboratory mutant strains of mice, flies, and worms are evolving at different rates among reptiles and mammals. This opens up many questions about how genetic variation in the IIS/TOR network collectively would alter reproduction and lifespan in natural populations of animals (including humans). They also discovered that in reptiles the IIS/TOR genes involved in activating the IIS/TOR network (hormones, receptors, and binding proteins) have extremely fast evolutionary rates relative to other genes in the genome. Further, they found signatures of positive selection and coevolution of the hormones, receptors, and binding proteins that suggest reptile- and mammal-specific interactions. In reptiles, positively selected sites cluster on the binding surfaces of insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and insulin receptor (INSR); in mammals, positively selected sites clustered on the IGF2 binding surface, suggesting these hormone-receptor binding affinities are targets of positive selection. This means natural selection is driving these proteins (and presumably their function) to change quickly among reptile species. These changes are predicted to affect how the hormones interact with the receptors, which may affect how the IIS/TOR network is activated and contribute to the variation seen in metabolic processes, modes of reproduction, and rates of aging.
This comparison of the IIS/TOR network between reptiles and mammals gives a very different perspective from previous work since this study focused on a large number of vertebrate species that have been evolving in natural populations (not in the laboratory). The study also allowed the investigators to include comparisons of the hormones, binding proteins, and receptors that activate the IIS/TOR cell signaling, which is not possible when comparing across vertebrates and invertebrates. This expanded view of the IIS/TOR network across the amniotes provides insight into how the IIS/TOR network can evolve among vertebrates. Additionally, it opens up new avenues for identifying specific targets (genes, mutations) to understand and potentially treat metabolic, reproductive, and aging processes and disorders in humans.
“Rapid Molecular Evolution across Amniotes of the ISS/TOR Network” was published in May in the Proceedings of the National Academy of Sciences.