In a groundbreaking study, Professor Joanna Masel from the University of Arizona and her team have taken a novel approach to unraveling the origins of the genetic code by analyzing protein data from LUCA—the Last Universal Common Ancestor. Departing from traditional methods that relied on prebiotic chemistry experiments or theoretical reasoning, Masel’s team leveraged advanced phylogenetic techniques to reconstruct ancestral amino acid sequences on an unprecedented scale. Their findings challenge long-held assumptions, revealing that amino acids like methionine and histidine were integrated into the genetic code much earlier than previously believed, suggesting a pivotal role for metals and sulfur in early life. In this Q&A, Professor Masel discusses how these insights reshape our understanding of life’s earliest molecular strategies and what they could mean for the search for life beyond Earth.
Your study looks at the order in which amino acids were added to the genetic code using protein data from LUCA (the Last Universal Common Ancestor). How is this approach different from previous methods, and why is it better?
Most previous methods performed laboratory experiments designed to mimic prebiotic chemistry, looked at abiotic presence in asteroids, or reasoned from first principles. But reasoning from first principles is obviously unreliable, and the genetic code didn’t evolve from non-life, it only evolved after complex life, including RNA, was already there. Some better previous approaches looked at which amino acids tend to be used at the conserved sites of a small set of proteins confirmed to be present in LUCA – these amino acids are then inferred to be early. We massively scaled up this approach, taking advantage of recent improvements in phylogenetic methods. We reconstructed the ancestral states of a much larger set of ancient amino acid sites, and compared them to a control group that is still very ancient without going all the way back to LUCA.
You found that certain amino acids, like methionine and histidine, were added to the genetic code earlier than we thought. What does this tell us about how metals and sulfur might have been important for early life?
Our results make perfect sense in hindsight. Histidine is the best and most used amino acid for binding metals such as copper and manganese. Either histidine or cysteine were needed to bind zinc. Binding these metals would have been critical for catalyzing early life reactions.
Methionine was thought to be late because it wasn’t one of the amino acids produced by the classic laboratory-based Urey-Miller experiment. But that experiment didn’t add sulfur, so of course it couldn’t be made. Interestingly, we also found that microbes that live in sulfur-rich environments today use more methionine, so this suggests that early life might have lived in a sulfur-rich environment.
Your study shows that smaller amino acids came first in the genetic code. How does this relate to the challenges early life forms faced in their environment?
We don’t know! It is a clue that future work will need to follow up on. Maybe it is simply that smaller things are cheaper to make. Maybe it has something to do with spatial constraints during translation.
Methionine and histidine are shown to have been added earlier than expected. What advantages might these amino acids have given early life in terms of survival or growth?
Methionine is a precursor of S-adenosyl methionine, or SAM. This molecule is important for a range of reactions, in particular for methylation. Today, methylation is a key part of regulating gene expression. Ancient RNA molecules also get methylated, which might have been important to early life.
Histidine would have helped with metal binding, as we mention above. It’s also interesting that there is a histidine-rich “HIGH” motif in class I of the amino acid synthetases that do the work of binding specific amino acids to carry out the genetic code. In other words, histidine seems to be important for amino acid binding – without which protein synthesis would not be possible.
The research highlights how hydrophobic amino acids are spaced apart in ancient proteins. Why is this important for how proteins fold and function, and what does it tell us about early protein structures?
Protein folding, of a 1-dimensional sequence of amino acid residues into a 3-dimensional structure, is hard. Amino acids that are “hydrophobic,” meaning that they bind one another rather than associating with water, are key to protein folding. But hydrophobic amino acids also raise the risks of misfolding, and of aggregating into a tangle with other proteins. Previous work in our lab has suggested that proteins that were born a long time ago tend to use a more sophisticated strategy than young proteins to resolve this double bind. The simple strategy of young proteins uses relatively few hydrophobic residues to avoid misfolding and aggregation, and clusters them together along the 1-dimensional sequence to enable at least a little bit of folding. The sophisticated strategy of old proteins intersperses hydrophobic residues along the protein sequence to reduce their tendency to misfold; this enables there to be more hydrophobic residues in total, and hence to have a more stable 3-dimensional fold. Our current paper shows that this difference in protein strategies exists even when comparing 4 billion year old protein domains to still-ancient 3 billion year old protein domains, and even when looking only in bacteria and archaea rather than in animals. It’s remarkable that the protein folding problem is so hard that it takes evolution billions of years to solve.
Your study suggests that glutamine was added to the genetic code later than other amino acids. What proof do you have for this, and why was it added later?
Glutamine is depleted in both LUCA and pre-LUCA sequences, ranking as the 19th amino acid in both age groups. We don’t know why it was so late, but other data is also consistent with it being late. In particular, many organisms today don’t have a proper glutamyl-tRNA synthetase to attach glutamine to its tRNA. This only evolved very late, in eukaryotes, and was then horizontally transferred to only some prokaryotes. Other prokaryotes, representing the ancestral method, load glutamate onto the glutamine’s tRNA, and convert the glutamate into a glutamine only after it is loaded.
You mention that early life might have thrived in sulfur-rich environments. How could this help us find life in places like Mars or Europa, where conditions might be similar?
So far, we only have one sample of life – here on Earth. Our best guess on where to search for life elsewhere is based on the conditions under which life here on earth got started. Sulfur richness might be one piece of the puzzle. It makes places like Mars and Europa even more appealing for our search for life since we have strong evidence indicating the abundance of sulfur on Mars’s surface and possibly in Europa’s subsurface ocean. Perhaps we can update NASA’s famous ‘Follow the water’ motto to ‘follow the water and the sulfur’.
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