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In football, defense keeps the opposing team in check. A similar strategy is at play inside our cells. Negative feedback loops (NFLs) help regulate how cells respond to signals, for example, dialing down activity when things get too intense. A new study from Vanderbilt University reveals that these molecular "defenders" evolve differently depending on where they sit in the signaling pathway.

Danial Asgari, a postdoctoral researcher in the Tate Lab, and Ann Tate, associate professor of Biological Sciences, a study in Molecular Biology and Evolution titled "How the Structure of Signaling Regulation Evolves: Insights from an Evolutionary Model."

Their findings show that NFLs acting closer to a cell's final decisions, such as turning genes on or off, are especially resistant to evolutionary change.

Downstream feedback loops operate near the cell nucleus, where small changes can significantly affect how genes are turned on or off. Upstream loops act earlier in the pathway, often at the cell surface, where they respond to signals from outside the cell.

"Our model predicts robust evolution of downstream negative feedback loops under all conditions, which signifies their crucial role in controlling gene expression," said Asgari. "This aligns with empirical observations showing a slower rate of change for proteins involved in downstream negative feedback loops."

The evolution of upstream regulators, by contrast, requires the alignment of several ducks in a row.

"I was surprised that upstream negative feedback loops evolve only under very specific conditions," he said. "One key finding of our study is the observation that degradation of signaling proteins facilitates the evolution of upstream NFLs."

To make the concept more accessible, Asgari offered an analogy. "Imagine an electric circuit. An upstream negative feedback regulates how much electricity flows into the circuit, which ultimately affects how much the LED lights up. A downstream negative feedback directly regulates the LED brightness without changing the input."

Tate sees the work as a key step in understanding how immune systems balance cost and control. She touched on the importance of pathway topology or the structure and order of interactions within a signaling pathway, essentially, how the molecular parts are connected.

"Our study suggests the strength of selection predicted by the model aligns with evolutionary rate statistics for NFL genes in real animals," said Tate.

"Until now, most studies on immune gene evolution have discussed variation in these statistics in terms of host-parasite arms races or trade-offs driving protein evolution; here we show that this variation could instead be driven by pathway topology."

These insights could have broader implications for understanding disease.

"We think that multiple layers of feedback regulation provide the opportunity to fine-tune this balance," Tate added. "But we should figure out the contribution of each layer in different disease contexts before we start messing with them in the clinic."