Rice University’s Peter Wolynes and his research team have made a significant discovery in how pseudogenes, which are specific genetic sequences, evolve. This paper was published by the Proceedings of the National Academy of Sciences on May 13. Led by Wolynes, who is the D.R. Bullard-Welch Foundation Professor of Science, professor of chemistry, biosciences, and physics and astronomy, as well as co-director of the Center for Theoretical Biological Physics.The team focused on studying the complex energy landscapes of de-evolved protein sequences corresponding to pseudogenes (CTBP). Pseudogenes are DNA segments that previously encoded proteins but have lost this ability due to sequence degradation, a process known as devolution. Devolution represents an unconstrained evolutionary process that occurs without the normal pressures that regulate functional protein-coding sequences. Despite their inactive state, pseudogenes provide insight into the evolutionary journey of proteins. The paper explains how proteins can de-evol.Researchers have discovered that a DNA sequence can lose its coding signal for a protein through mutations or other mechanisms, which can result in a sequence that cannot fold even as the DNA continues to mutate. The study focused on junk DNA in a genome that has de-evolved, and found that mutation accumulation in pseudogene sequences disrupts the stabilizing interactions network, making it difficult for these sequences to fold into functional proteins if they were to be translated. Despite this, the researchers also noticed that some mutations unexpectedly stabilized the folding of pseudogenes.
Genes can undergo mutations that lead to the formation of pseudogenes, which may come with changes to their original biological functions.
The researchers have found specific pseudogenes, like cyclophilin A, profilin-1, and small ubiquitin-like modifier 2 protein, in which stabilizing mutations have occurred in important regions for binding to other molecules and other functions. This indicates a delicate balance between protein stability and biological activity.
Furthermore, the study emphasizes the fluid nature of protein evolution, as some genes that were previously pseudogenized may eventually regain their protein-coding function over time, even after experiencing multiple mutations.
Advanced techniques were used in the study to analyze the changes in genes at a molecular level.The scientists used computational models to analyze how physical folding landscapes and evolutionary landscapes of pseudogenes interact. Their results suggest that the funnel-like shape of folding landscapes is influenced by evolution.
“Proteins can lose their ability to fold properly over time due to mutations or other factors,” explained Wolynes. “Our research provides the first concrete proof that evolution impacts the folding of proteins.”
In addition to Wolynes, the team of researchers includes Hana Jaafari, a graduate student in applied physics, and Carlos Bueno, a postdoctoral associate at the CTBP.The research was conducted by a team of individuals including University of Texas at Dallas graduate student Jonathan Martin, Faruck Morcos who is an associate professor in the Department of Biological Sciences at UT-Dallas, and CTBP biophysics researcher Nicholas P. Schafer. This study has implications that go beyond theoretical biology and could potentially be used in protein engineering, Jaafari mentioned. It would be interesting to see if our results can be confirmed in a lab, to observe what happens to the pseudogenes that were more physically stable. Jaafari also added that they have an idea based on their analysis, but it would be compelling to have some experimental validation.”
