Coordinated adaptive changes in insulin, insulin receptor, and inceptor genes in hystricognath rodents

Insulin is a central regulator of glycemia and is highly conserved across mammals. However, hystricognath rodents represent a notable exception, exhibiting insulin proteins that diverge significantly in both sequence and physiological function. Previous studies have shown that this divergence is partially driven by positive selection acting on residues involved in the second binding site of the hormone and in hexamer formation, which is critical for insulin storage in mammals. Inceptor (encoded by the gene ELAPOR1) is a recently discovered regulator of the insulin pathway that interacts with proinsulin, insulin, the Insulin receptor (Insr), and the Insulin-like growth factor 1 receptor (Igf1r). Inceptor functions within pancreatic {beta}-cells, where it promotes clathrin-mediated endocytosis of Insr and directs cytoplasmic insulin and proinsulin to lysosomal degradation. Using a comprehensive dataset of mammalian sequences, we tested for positive selection in the genes Ins, Insr, Igf1r, and ELAPOR1 using maximum likelihood models. Significant signals of positive selection were detected in hystricognath rodents for Ins, Insr, and ELAPOR1, but not for Igf1r. In Ins, positively selected sites were concentrated in the second binding site and in regions involved in hexamer formation, along with an additional site in the C-peptide. In Insr, selected sites were primarily located in the ectodomain, particularly in regions that interact with the second binding site of the insulin molecule. In ELAPOR1, selected sites were concentrated in the signal peptide and at the boundary between the second cysteine-rich domain and the mannose 6-phosphate receptor region. Together, these findings provide strong evidence that natural selection has shaped multiple components of the insulin signaling pathway, contributing to the functional divergence observed in hystricognath rodents.