Existing models of genetic code evolution need revision, study finds

The genetic code acts as life’s instruction manual, telling cells how to build proteins from DNA and RNA. Though it’s a marvel of molecular precision, the path it took to evolve remains unclear. Fresh findings from a group of researchers from the University of Arizona are now shaking up the long-held assumptions of how this code came to be.

Sawsan Wehbi, a Ph.D. student in genetics, led the study that questions how the genetic code evolved. Published in PNAS, the work argues that current models misrepresent the order in which amino acids—protein’s key pieces—joined the code. If true, this would call into question decades of assumptions about molecular evolution.

“The genetic code is nearly optimal for numerous functions,” said Joanna Masel, the paper’s senior author. “It’s a mind-bogglingly complicated process, yet it must have evolved in stages. Our findings challenge the conventional narrative of its evolution.” Masel is a professor of ecology and evolutionary biology.

The research highlights three major takeaways. First, smaller amino acids likely entered the code before larger, more complex ones. Second, amino acids that bind metals may have appeared earlier than scientists thought. Third, the modern code likely replaced simpler, now-extinct codes along the way. These shifts push scientists to rethink the long-held timeline.

Many of today’s theories date back to the famous 1952 Urey-Miller experiment, which mimicked early Earth conditions to show how life’s parts could form. While groundbreaking, the experiment left out one key ingredient: sulfur. That omission had lasting effects on how scientists viewed certain amino acids.

“Sulfur was omitted from the experiment’s ingredients, so it’s not surprising that sulfur-containing amino acids didn’t appear,” said Dante Lauretta, a co-author and planetary scientist. “This oversight has profound implications for astrobiology, especially in the search for life on sulfur-rich worlds like Mars or Europa.”

Instead of relying on lab simulations, the new study looked at how proteins evolved across time. The team focused on protein domains—short, functional stretches—rather than full proteins. This approach helped them isolate which pieces came first.

They studied sequences dating back to the last universal common ancestor, or LUCA, which lived around four billion years ago. More than 400 protein domain families were linked to LUCA, and over 100 traced back even earlier. These patterns helped the team map the genetic code’s path with fresh precision.

Wehbi likened protein domains to parts of a car. “If a protein is a car, a domain is like a wheel,” she said. “Wheels have been around much longer than cars.”

By comparing ancient and moderately ancient protein sequences, the researchers deduced when specific amino acids likely joined the genetic code. Amino acids more prevalent in ancient sequences were likely incorporated earlier, while those appearing less frequently were added later.

The findings overturn traditional views, particularly regarding amino acids like methionine, histidine, and aromatic ring structures such as tryptophan and tyrosine. Methionine and histidine, once thought to be late additions, are now considered early components due to their roles in metal-binding and purine-like structures.

The early presence of sulfur-rich methionine aligns with its role in essential biochemical pathways, such as the synthesis of S-adenosylmethionine, a critical molecule in cellular metabolism.

Histidine’s early inclusion is particularly significant given its importance in enzymatic activity. Although often classified as late due to its supposed unavailability in prebiotic environments, histidine’s structural resemblance to purines suggests it could have been biotically synthesized by early life forms. Its conservation in enzyme active sites underscores its evolutionary importance.

The study also highlights the role of aromatic amino acids, which were abundant in sequences predating LUCA. These findings hint at earlier genetic codes distinct from the modern one. “This gives clues about other genetic codes that existed before ours and have since disappeared,” Masel explained. “Early life seems to have favored aromatic structures.”

The research critiques previous methods of inferring amino acid recruitment, which often relied on abiotic availability. For instance, the Urey-Miller experiment’s exclusion of sulfur-containing amino acids misrepresented their evolutionary timeline.

Subsequent experiments have shown that sulfur-rich environments could produce amino acids like methionine and cysteine abiotically, challenging the consensus.

Furthermore, histidine’s early availability, despite its complex synthesis, suggests it may have been biotically produced by organisms already utilizing peptides. The study proposes that the evolutionary timeline should consider the biochemical needs of early life rather than just prebiotic abundance.

To infer the genetic code’s evolution, the team used statistical tools to analyze ancient protein sequences. Their approach differed from previous studies by focusing on protein domains rather than entire proteins.

Protein domains, which can function and evolve independently, offer a more precise understanding of the genetic code’s development. This method revealed that ancient proteins had distinct amino acid compositions compared to those emerging later.

The findings also challenge the “consensus” order of amino acid recruitment, which has limited predictive power. Smaller amino acids were added earlier, followed by those with specific biochemical properties, like metal-binding capabilities. The study emphasizes that evolutionary evidence, rather than abiotic synthesis experiments, should guide future research.

These insights have implications beyond Earth. The study’s findings on sulfur-rich amino acids could inform the search for extraterrestrial life.

“On planets and moons with sulfur-rich environments, such as Enceladus and Europa, we might find analogous biogeochemical cycles or microbial metabolisms,” Lauretta noted. “Understanding these processes could refine what we look for in biosignatures, improving our chances of detecting life beyond Earth.”

The genetic code’s evolution remains an intricate puzzle, but this study represents a significant step forward. By revising long-held assumptions and emphasizing evolutionary evidence, researchers are uncovering a more accurate narrative of how life’s blueprint came to be.

This work not only enhances our understanding of life on Earth but also guides the search for life in the universe.

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