UAB study finds how genetic variation in IIS/TOR molecular network may regulate variation in metabolism

New research from the University of Alabama at Birmingham finds genetic variants that occur in nature and lay the groundwork for future studies of diseases and treatments in humans.

The insulin/insulin-like signaling and target of rapamycin (IIS/TOR) molecular network is an important group of genes that integrates signals from the environment, such as levels of stress or nutrition, to regulate growth, reproduction, metabolism and aging, says senior study author Tonia Schwartz, Ph.D., postdoctoral fellow in the UAB Office of Energetics, of findings published in the Proceedings of the National Academy of Science.

Schwartz says reptiles are the group of animals most closely related to mammals, but they differ — sometimes dramatically — in their metabolic processes, how they age and how they reproduce.

"Comparing studies between reptiles and mammals can help us to understand the genetic basis for these traits," Schwartz said. "Therefore, we wanted to conduct a large-scale evolutionary analysis to test whether the genes in the IIS/TOR network were evolving differently among reptiles and mammals."

The researchers sequenced the genes of 18 reptiles and used these data along with previously published gene sequences to compare how 61 genes from the IIS/TOR network were evolving among 32 mammals and 34 reptiles.

"We found that many of the critical genes in the IIS/TOR network are evolving at different rates between reptiles and mammals," Schwartz said.

Also, the researchers found that, in reptiles, the IIS/TOR genes involved in activating the IIS/TOR network — for example, the hormones, receptors and binding proteins — have exceptionally fast evolutionary rates relative to other genes in the genome.

"Generally speaking, this means that these proteins, and presumably their function, are more variable among reptile species than we would have expected," Schwartz said. "More specifically, the changes in these proteins are predicted to affect how the hormones interact with the receptors. This may affect how the IIS/TOR network is activated and may possibly contribute to the variation we see in metabolic processes, modes of reproduction and rates of aging."

The IIS/TOR network has been well-studied, but these studies had largely been restricted to laboratory models such as mice and fruit flies, Schwartz says. Based on results from this relatively narrow scope, the researchers expected to find minimal genetic variation in this network.

"We were surprised to find considerable natural genetic diversity in this network, particularly in the more critical or core genes," Schwartz said. "We were also surprised and excited to see the protein changes were concentrated on the interacting surfaces of the hormones and their receptors — suggesting they may be altering how the IIS/TOR network may be activated, or responding to environmental cues, among the different species."

This study is currently the largest comparative study of the IIS/TOR network, in both the number of genes and the number of species, Schwartz says.

"This study provides a critical step toward understanding how genetic variation in the IIS/TOR network may regulate variation in metabolism, modes of reproduction and rates of aging," Schwartz said. "It lays the groundwork for future research to identify natural genetic variants that may work together to alter the function of this network, which may lend insight to metabolic and aging diseases and treatments."

Future research will focus on the functional significance of the changes we see to the hormones and the receptors across the mammal and reptile species, particularly in relation to affecting reproduction and rates of aging.