Rice University’s Peter Wolynes and his research team have revealed a breakthrough in understanding how specific genetic sequences, known as pseudogenes, evolve. His article was published on May 13 by the Proceedings of the National Academy of Sciences.
Led by Wolynes, the DR Bullard-Welch Foundation Professor of Science, professor of chemistry, biosciences, physics, and astronomy, and co-director of the Center for Theoretical Biological Physics (CTBP), the team focused on deciphering the planet’s complex energy landscapes. sequences of putative evolved proteins corresponding to pseudogenes.
Pseudogenes are segments of DNA that once encoded proteins but have since lost their ability to do so due to sequence degradation, a phenomenon known as devolution. Here, devolution represents an unrestricted evolutionary process that occurs without the usual evolutionary pressures that regulate functional protein-coding sequences.
Despite their dormant state, pseudogenes offer a window into the evolutionary journey of proteins.
“Our paper explains that proteins can evolve,” Wolynes said. “A DNA sequence can, through mutation or other means, lose the signal that tells it to code for a protein. The DNA continues to mutate but it does not have to lead to a sequence that can fold.”
The researchers studied junk DNA in a genome that has evolved. Their research revealed that an accumulation of mutations in pseudogene sequences generally disrupts the native network of stabilizing interactions, making it difficult for these sequences, if translated, to fold into functional proteins.
However, the researchers observed cases in which certain mutations unexpectedly stabilized the folding of pseudogenes at the cost of altering their previous biological functions.
They identified specific pseudogenes, such as cyclophilin A, profilin-1, and small ubiquitin-like modifying protein 2, where stabilizing mutations occurred in regions crucial for binding to other molecules and other functions, suggesting a complex balance between protein stability and biological activity.
Furthermore, the study highlights the dynamic nature of protein evolution, as some previously pseudogenized genes can regain their protein-coding function over time despite undergoing multiple mutations.
Using sophisticated computational models, the researchers interpreted the interaction between the physical folding landscapes and the evolutionary landscapes of pseudogenes. Their findings provide evidence that the funnel-like character of folding landscapes comes from evolution.
“Proteins can evolve and their ability to fold is compromised over time due to mutations or other means,” Wolynes said. “Our study provides the first direct evidence that evolution is shaping protein folding.”
Along with Wolynes, the research team includes lead author and applied physics graduate student Hana Jaafari; Carlos Bueno, postdoctoral associate at CTBP; University of Texas at Dallas graduate student Jonathan Martin; Faruck Morcos, associate professor in the Department of Biological Sciences at UT-Dallas; and CTBP biophysics researcher Nicholas P. Schafer.
The implications of this research extend beyond theoretical biology with potential applications in protein engineering, Jaafari said.
“It would be interesting to see if someone in a lab could confirm our results to see what happens to the pseudogenes that were more physically stable,” Jaafari said. “We have an idea based on our analysis, but it would be compelling to get some experimental validation.”