April 13, 2024

How did the first RNA molecules evolve on prehistoric Earth?

Before DNA-containing organisms colonized Earth, there was already a wide variety of simple RNA molecules on prehistoric Earth. Researchers have now recreated in the laboratory the conditions under which RNA molecules gain the ability to enhance each other. These conditions mark the beginning of evolution toward more complex organisms. According to this, evolution at the molecular level began long before cells existed, with individual RNA enzymes reliably transcribing other RNA molecules. With this knowledge, it is now possible to recreate the previous “RNA world” in the laboratory.

Life on Earth evolved billions of years ago from just a few small building blocks of life. Long before cells existed, they already contained various RNA molecules. During an era in Earth's history, these organisms dominated terrestrial life, according to the common scientific theory “the RNA world.” Some RNA molecules took over the task of subsequent DNA by storing genetic information and transmitting it from generation to generation. Other RNA molecules, such as later evolved proteins, act as enzymes that catalyze and accelerate biochemical reactions. These RNA enzymes are also called ribozymes and still exist to a lesser extent today. But what role did they play in the “RNA world” at that time?

Evolution of RNA molecules

A team led by Nikolaos Papastavrou of the Salk Institute in California examined this in more detail. “We're tracing the beginning of evolution,” says lead author Gerald Joyce, also of the Salk Institute. “We asked ourselves when did life acquire the ability to improve itself,” Papastavrou adds. Specifically, the researchers analyzed the conditions necessary for individual RNA molecules to evolve further so that optimal building blocks of life could arise from them. To do this, researchers developed an RNA enzyme whose job is to catalyze the replication of other RNA molecules: the so-called RNA polymerase. This ribozyme was initially very simple, could only copy short sequences of RNA and made many mistakes. Accordingly, Papastavrou and his colleagues gradually modified the RNA enzyme using directed evolution. Dozens of rounds of mutagenesis and selection have led to the emergence of enzyme variants that are able to do their job better, better, and with fewer errors.

Visualization of RNA molecules undergoing evolution, colored by successive generations. If the RNA polymerase functions unreliably, the transcribed RNA sequence acquires many mutations and thus loses its function over time (above, from blue to purple). However, with more reliable RNA polymerases, only a few errors and beneficial mutations occur, making the transcribed RNA sequences increasingly better (below, yellow to red). © Salk Institute

This showed that from a certain point onwards, the RNA enzyme was improved to the point that it could also reliably transcribe longer RNA molecules. However, there was still an error rate of about ten percent, which allowed for useful variations and mutations to exist in the replicated organism. The sequence of the transcribed RNA changed over several rounds of transcription, so that the second RNA molecule was eventually able to do its job better, the researchers reported. However, if researchers used native, unoptimized, and unreliable RNA polymerase, the RNA sequence it copied would lose its function over time because too many mutations accumulated.

Coevolution laid the foundation for today's organisms

Overall, the study suggests that an “RNA world” already existed on prehistoric Earth, where the evolution of RNA enzymes and other RNA molecules proceeded in parallel. Without RNA polymerases with high fidelity and low error tolerance, more sophisticated RNA molecules would not have emerged, and without the evolution of RNA there would not have been higher organisms composed of more complex molecules and cells, including humans. “By revealing these new capabilities of RNA, we are revealing the potential origins of life itself and showing how simple molecules may have paved the way for the complexity and diversity of life we ​​see today,” Joyce explains.

Based on the results, Papastavrou and his colleagues hope that ancient RNA-based creatures can now be reconstructed in the laboratory. This could then provide further insights into the beginning of life on Earth or even other planets. These follow-up studies could also elucidate environmental conditions on prehistoric Earth that could have fueled the development of the “RNA world.”

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Source: Nikolaos Papastavrou (Salk Institute) et al., Proceedings of the National Academy of Sciences (PNAS), doi: 10.1073/pnas.2321592121