A new study in Current Biology (PDF) sheds light on how a critical protein underlying hearing evolved to perform its specialized role in vertebrate sensory systems—offering a rare link between molecular evolution and cellular function.
The work, led by Nurunisa Akyuz, former research associate in the Neurobiology Department in David Corey’s lab, and supported by evolutionary analysis from Trey Scott, postdoctoral fellow in the labs of Naomi Pierce (OEB) and MCB’s Nicholas Bellono, focuses on TMC1, a protein essential for mechanotransduction in hair cells—the sensory receptors that convert sound-induced mechanical forces into electrical signals.
Hair cells, found in the auditory and vestibular systems of vertebrates, rely on mechanically sensitive ion channels to detect motion. While TMC1 has been identified as a core component of this process, how it acquired its specialized role in hearing has remained unclear.
“From a molecular and cellular biology perspective, this work links evolutionary changes in a specific protein domain to functional consequences in hair cells, connecting sequence variation to cellular mechanotransduction,” said Akyuz. “It’s an example of how molecular features shape cellular function.”
From structure to evolution—and back again
The study integrates structural predictions, physiology, and evolutionary biology to reconstruct how TMC1 evolved. TMC proteins are ancient: they appear in some of the earliest animals, such as sponges, and even in their unicellular relatives, the choanoflagellates. Long before hearing, before even the emergence of complex animal organization.
Using the AlphaFold artificial-intelligence system for protein modeling alongside comparative genomics, the team identified key structural changes that emerged alongside the evolution of vertebrate hair cells.
“From an evolutionary perspective, we are highlighting that evolution didn’t invent a new protein for hearing,” Akyuz said. “Instead, it adapted an existing structural framework by modifying key regions.”
These modifications were concentrated in extracellular domains of the protein—regions positioned to interact with mechanical forces transmitted through hair cell structures known as tip links.
The timing of these structural changes is notable: they appear to coincide with the emergence of hair cells as a vertebrate innovation. In early vertebrates, including fish, hair cells are not only found in the inner ear but also along the lateral line, where they detect movement and vibrations in the surrounding water.
As vertebrates moved onto land, TMC1 continued to evolve. In animals like frogs, birds, and mammals, parts of the protein changed over time, pointing to evolutionary fine-tuning and suggesting that incremental molecular adaptations helped enable the evolution of hearing.
Tracing evolutionary history in protein sequences
Scott led the evolutionary analysis that underpins the study. By mining genomic data across species, Scott reconstructed the gene family history of TMC proteins, identifying duplication events that gave rise to the TMC1 lineage and mapping where key evolutionary changes occurred.
“This is a large protein family that has been duplicated many times,” said Scott. “We wanted to understand whether those duplications happened at important evolutionary transitions—like the origin of vertebrates—and whether specific parts of the protein were under selection.”
His analysis revealed that TMC1 and its close relatives are largely restricted to vertebrates, supporting the idea that their specialization is tied to the evolution of hair cells. He also identified sites within a critical extracellular loop—between transmembrane domains 1 and 2—that show signatures of positive selection in mammals.
“That suggests adaptation—something functionally important is happening in those regions,” Scott explains. Notably, these evolutionary changes coincide with the emergence of high-frequency hearing and other auditory innovations in mammals, though the study stops short of drawing a direct causal link.
A collaborative, cross-disciplinary approach
The project brought together complementary expertise in structural biology and evolutionary genomics. Akyuz and Scott worked closely to interpret how sequence-level changes might translate into functional consequences. “This integrated approach really opens up new ways of thinking about how proteins acquire new functions,” Akyuz adds.
Scott added that the study highlights a broader opportunity in biology: using evolutionary signals to guide functional discovery. “If adaptation happens, you should be able to see those signals in the protein,” he said. “And that can help pinpoint the regions that actually matter for function.”
In this study, these insights were further tested in native hair cells, linking molecular changes to channel function in a physiological context and drawing on specialized expertise.
Opening new questions in hearing biology
Beyond reconstructing the evolutionary history of TMC1, the findings raise new mechanistic questions. One key possibility is that the extracellular domain identified in the study may directly participate in the gating of the channel by tip links—the molecular structures that transmit mechanical force in hair cells.
“If that’s the case,” Akyuz noted, “then its evolution could have contributed to increased sensitivity in mammalian hearing.”
While further work will be needed to test these ideas experimentally, the study provides a framework for linking evolutionary changes to biophysical mechanisms.
(PDF)
