Scientists clock a driving factor in the evolution of error correction

All complex biological systems—like the DNA, RNA and proteins constantly being copied and built within our cells—are prone to errors. That means as life evolved to be more elaborate, it also had to evolve error-correcting strategies.

Scientists have long assumed that the time spent correcting errors is simply an unavoidable cost to organisms. But in a new study published in Science, a team of UChicago physicists and chemists found that fixing errors can actually make the synthesis process faster overall—suggesting that speed alone could be the factor driving the evolution of error correction.

"We found that proofreading mechanisms can evolve just because biology wants to go fast, without having to care about accuracy," said co-first author Kabir Husain, a postdoctoral researcher at UChicago at the time of the research and now faculty at University College London.

"These results imply that error correction is easier to evolve than previously thought and could have arisen earlier during the origins of life."

The wrong puzzle piece

A common type of error-correcting mechanism in biology is called kinetic proofreading. For example, if errors turn up when cells are making new DNA, enzymes can cut out incorrect nucleotides. They can also backtrack to fix errors during RNA transcription, or disassemble incorrectly made protein complexes to try again.

Fixing these mistakes takes time. Scientists have widely assumed that the error correction has to be done despite it slowing down the process, because mistakes could be so harmful to the organism. (Uncorrected errors, for example, are often the basis of cancer.)

However, this assumption does not take into account that the errors "themselves" inherently slow down the process.

"For example, the assembly of a complex structure such as the ribosome can be stalled when some step in the assembly process goes awry," said co-author Jack Szostak, University Professor in the Department of Chemistry. "In such cases, the fastest way to complete the assembly process may be to go back a few steps and start over."

The UChicago team became interested after an unrelated experiment in the lab of Arvind Murugan, associate professor in the Department of Physics and the James Franck Institute, which studies the essential functions of life—learning, self-replication, and evolution—in the simplest possible systems.

Murugan, Husain, and other lab members were running experiments looking at the mutation rate of DNA polymerase, which is the molecular machine that copies DNA.

They found that mutated polymerases that made more mistakes slowed down the process, which was the opposite of what they had intuitively thought—that doing the job "sloppily" would speed it up.

This effect, called stalling, happens when an uncorrected error slows down subsequent steps.

Husain compared it to placing the wrong piece in a jigsaw puzzle. "You're stuck, because now the next piece is really hard to put in, and because of that, it takes you longer to finish the puzzle."

Around that time, Riccardo Ravasio, a postdoctoral researcher in Murugan's lab and co-first author on the paper, joined the team. Ravasio developed a physics-based computational model, stripped of biological elements, to test whether stalling takes longer than error correction.

The model is an extension of a fundamental classical physics model of kinetic proofreading introduced over 50 years ago.

"We turned the model on its head by introducing this new ingredient of stalling after mismatches, to investigate whether there actually is a trade-off between speed and accuracy," said Ravasio.

Using this model, the team simulated the evolution of a DNA polymerase. They found that proofreading took less overall time than stalling—indicating that evolutionary selection for speed alone leads to more proofreading and improved accuracy, regardless of how harmful or harmless errors might be.

The study also raises further questions about the stalling effect, found to be widespread in biological processes: "Is stalling a property that can itself evolve?" asked Ravasio. "What's driving the emergence of stalling in the first place?"

A growing genome

The highly collaborative study, which leveraged the different backgrounds, knowledge, and skills of scholars from UChicago's Physics Department and Chemistry Department, University College London, Maynooth University, California Institute of Technology, and Université PSL, contributes to UChicago's Origins of Life initiative.

The results offer a new advancement toward understanding how life developed on Earth and the potential for life elsewhere—the mission of the Chicago Center for the Origins of Life. The center unites chemists, physicists, astronomers, and Earth and planetary scientists to investigate questions so immense that no one discipline can answer.

"One of the many puzzles about the origin and early evolution of life is how and why the fidelity of genome replication increased so that larger and larger amounts of information could be transmitted from generation to generation," said Szostak, director of the Center for the Origins of Life.

"The surprising results of our study, which show that selection for speed of replication alone can lead to the evolution of error-correcting mechanisms, independent of selection for maintenance of the underlying information, gives a new perspective on the evolution of error correction."

The project is a good example of what happens when UChicago brings different kinds of scientists together. "My group had been all-theory until we tried some wet-lab experiments and couldn't make sense of our results," said Murugan.

"A chance conversation with Jack during his recruitment to the Origins initiative made us realize that this was something bigger, and we now have several follow-ups that span physics, chemistry and evolution."