Rapid molecular evolution across amniotes of the IIS/TOR network

Abstract

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. We conducted an extensive evolutionary analysis of the IIS/TOR network across 66 amniotes with 18 newly generated transcriptomes from nonavian reptiles and additional available genomes/transcriptomes. We uncovered rapid and extensive molecular evolution between reptiles (including birds) and mammals: (i) the IIS/TOR network, including the critical nodes insulin receptor substrate (IRS) and phosphatidylinositol 3-kinase (PI3K), exhibit divergent evolutionary rates between reptiles and mammals; (ii) compared with a proxy for the rest of the genome, genes of the IIS/TOR extracellular network exhibit exceptionally fast evolutionary rates; and (iii) signatures of positive selection and coevolution of the extracellular network suggest reptile-and mammal-specific interactions between members of the network. In reptiles, positively selected sites cluster on the binding surfaces of insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and insulin receptor (INSR); whereas in mammals, positively selected sites clustered on the IGF2 binding surface, suggesting that these hormone-receptor binding affinities are targets of positive selection. Further, contrary to reports that IGF2R binds IGF2 only in marsupial and placental mammals, we found positively selected sites clustered on the hormone binding surface of reptile IGF2R that suggest that IGF2R binds to IGF hormones in diverse taxa and may have evolved in reptiles. These data suggest that key IIS/TOR paralogs have sub-or neofunctionalized between mammals and reptiles and that this network may underlie fundamental life history and physiological differences between these amniote sister clades.insulin signaling | insulin growth factor | molecular evolution | rapamycin T he last 20 y has provided overwhelming support that the insulin-and insulin-like signaling/target of rapamycin (IIS/TOR) molecular network responds to stress and nutrients and underlies a wide range of physiological functions (1); cancer, metabolic syndrome, and diabetes (2); and the timing of life events (e.g., growth, maturation, reproduction, and aging) (3). The vertebrate IIS/TOR network consists of peptide hormones, binding proteins that regulate hormone bioavailability, and cell membrane receptors (hereafter, extracellular proteins of the IIS/TOR network) that induce an intracellular signaling cascade (hereafter, intracellular proteins of the IIS/TOR network) to stimulate cell proliferation, survival, and metabolism (Fig. S1). The core intracellular signal transduction genes in this network are largely conserved across deep phylogenetic time (4, 5). In contrast, genes encoding the IIS/TOR extracellular network have diverged in the vertebrate lineage (6-8) and may have variable roles among taxa (9, 10). Despite its central rol...

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