Home Cellular science Screen of 250,000 species reveals genetic code changes

Screen of 250,000 species reveals genetic code changes


TThe genetic code that dictates how genetic information is translated into specific proteins is less rigid than scientists have long assumed, according to research published today (November 9) in eLife. In the article, scientists report examining the genomes of more than 250,000 species of bacteria and archaea and finding five organisms that rely on an alternate genetic code, signifying branches of evolutionary history that do not have not been fully explained.

The genetic code refers to how the nucleotide base sequences of DNA lead to specific chains of amino acids during the process of protein synthesis. To perform this synthesis, ribosomes read strands of mRNA – copies of pieces of the organism’s genome – in pieces of three bases at a time. Each three base sequence, known as a codon, binds to a specific transfer RNA (tRNA) that carries a corresponding amino acid to the ribosome to add it to the protein chain. An organism with an alternate genetic code, like the five new cases found by the study authors, has codons that correspond to different amino acids than the standard genetic code used by the vast majority of known life forms.

“The genetic code has been set in stone for 3 billion years,” said study co-author Yekaterina Shulgina, a systems biology graduate student at Harvard University. The scientist. “The fact that some organizations have found a way to change it really fascinates me. Changing the genetic code requires changing old and important molecules like tRNAs that are so fundamental to the functioning of biology. “

As such, the code was believed to be largely preserved in all life forms, with scientists finding an occasional exception in recent decades of research. In addition to finding five new alternative genetic codes, the team also verified seven more that had been discovered one by one in the past, bringing the total number of known exceptions in bacteria to 12.

“I am happy to see that all of the results we have achieved so far have come out in [the new paper]Said Dieter Söll, a biochemist at Yale University, who did not work on the study. The scientist. Söll has been studying the evolution of the genetic code for decades and was the first to find an alternative genetic code in bacteria. The team’s methodology was “very good,” he says, not least because of how it illustrates that “the genetic code is extremely flexible.”

“Getting back everything we already knew and doubling the number of known reassignments” was particularly impressive, says University College Dublin professor of genomic evolution Kenneth Wolfe, who also did not work on the study. “What they’re looking for is really rare.

Shulgina and study co-author Sean Eddy, a Harvard biologist and Howard Hughes Medical Institute researcher, have developed an algorithm called Codetta, named after the Rosetta Stone, which can screen an organism’s genome and predict which acids amino its codons will add to a given protein. . The algorithm quickly selects a genome and compares it to the body’s proteins in a database called Pfam. If enough variations from the standard code appear consistently, Codetta signals the organism as potentially using another amino acid for a particular codon. From there, researchers can experimentally validate his work by looking for the predicted tRNA in the body.

Codetta excels at finding almost identical genetic codes to the standard. For example, all newly discovered reassignments affect arginine, which is normally encoded by the codons AGG, CGA, and CGG. In some of the newly discovered alternative genetic codes, these codons are reassigned to the amino acid tryptophan, which is already associated with the similar codon TGG.

Before the new study, all known alternative genetic codes in bacteria involved changing a “stop” codon that tells the cellular machinery that it has reached the end of a protein to a codon associated with an amino acid. The new results reveal the first alternative genetic codes in bacteria that represent sense codon reassignment, that is, the change of a codon from one amino acid to another.

Identifying these alternate codes is important, Eddy says, because scientists who predict which proteins an organism will synthesize based on its genome do so assuming the standard genetic code is involved. accuracy of these predictions and will prevent coding errors in databases as more genomes are sequenced.

Changing the genetic code requires changing old and important molecules like tRNAs that are so fundamental to the functioning of biology.

—Yekaterina Shulgina, Harvard University

But these changes shouldn’t happen under normal circumstances, says Eddy.

“If you try to change the meaning of a codon, you are essentially introducing simultaneous mutations throughout the genome,” Eddy said. The scientist. “Every place that codon is used, you’ve just substituted an amino acid. It’s just mind-boggling an organism can survive that. Stop codon changes are considerably less ‘dramatic,’ Eddy adds, because change a stop codon into a sense codon does not really change the function of a protein, but simply extends its tail.

Part of the reason changes occur, explains Shulgina, is that some bacterial genomes may have a low makeup of some nucleotides compared to others. This reduces the use of codons that are based on these nucleotides to almost zero, making it easier for an organism to survive changes without drastically altering too many proteins.

“At least in bacteria, it seems that these kinds of forces could explain why the genetic code evolved this way,” says Shulgina. “It could be totally different if we looked at other life forms like eukaryotes.” Exceptions to the standard genetic code have been found in unicellular eukaryotes like yeast, but experts expect alternative codes to be rare in more complex eukaryotic organisms.

It is difficult to trace why these alternative genetic codes emerged during the history of evolution, according to several researchers The scientist, largely because humans couldn’t see it happening. But the authors have some assumptions.

In one case, Shulgina identified a bacterium that uses the same alternate code as a bacteriophage virus that infects it, indicating that the bacteria apparently developed an alternate code that prevented the hijacking of its cellular machinery – and that the phage has perhaps then made the same adaptation to follow his host.

To this end, bacteria and archaea represented the simplest test for Codetta. Shulgina, Eddy and other researchers say they are eager to see what the algorithm finds in eukaryotic life; running a screen on a eukaryotic genome, however, would be difficult due to the amount of noise that would be added to the signal. Eukaryotic genomes are teeming with non-functional pseudogens, says Shulgina, which should either be filtered out or factored into a Codetta update lest they confuse the algorithm.

The team also ran Codetta on the genome of yeast, a eukaryote known to have alternative genetic codes, and made a new discovery that validated its predictions for bacteria. At one point, the algorithm was not secure enough to assign an amino acid to a particular codon. Upon further investigation, it turned out that yeast uses the same codon to encode two different amino acids.

“My method is not designed to find that; it was designed to find different encodings, not ambiguous encodings, ”explains Shulgina. “Codetta didn’t want to pick any amino acid for this codon, so in a sense it failed very correctly.”

Eddy and Shulgina plan to refine the algorithm and say knowing these limits ahead of time will allow other researchers to resume their work and perform their own genomic screens. To this end, Shulgina and Eddy made Codetta available on GitHub to any researcher who would like to use it or develop his own version.

“As we are only scratching the surface of true microbial biodiversity, I think it is very likely that Codetta will be useful in discovering additional codon reassignments,” Pavel Baranov, University of Cork biochemist, who did not work on the study, says The scientist by email. “I can’t wait to try it for myself.”

Yet Codetta’s computational predictions need to be validated with mass spectroscopy and other tools, says University of Göttingen systems biologist Martin Kollmar. The scientist.

In particular, Kollmar would have liked to see more examples of experimental verification, such as double checking that proteins synthesized by alternative genetic codes had the expected amino acid composition. But, he adds, “it is hard work and beyond the scope of this article.”

Meanwhile, each researcher who spoke with The scientist said they expect Codetta to continue to find new exceptions to the rules set out by the genetic code.

“This study is a beautiful illustration that there is hardly anything universally preserved [across all life]”Says Antonis Rokas, a biologist from Vanderbilt University, who was not involved in the work.” Biology is just, in some ways, the science of exceptions.

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