But the biggest surprise was that the viruses had an enzyme polymerase dedicated to the pairing of Z bases with T during DNA replication. “It was like a fairy tale,” said Marlière, who hoped to find such a polymerase. “Our wildest dreams have come true.”
That’s because scientists have discovered other examples of bacteriophages that make nucleotide substitutions, this is “the first polymerase that has really been shown to selectively exclude a canonical nucleotide,” said Peter Weigele, a New England Biolabs researcher who studies the biosynthesis of noncanonical bases. The system has evolved to allow for “reprogramming,” Romesberg said – one that could potentially provide new insights into how polymerases work and how to create them.
Z and other modified DNA bases appear to have evolved to help viruses evade the defenses by which bacteria break down foreign genetic material. The perpetual arms race between bacteriophages and their host cells probably provides enough selection pressure to affect something seemingly “sacrosanct” like DNA, according to Romesberg. “Right now, everyone thinks that modifications only protect DNA,” he said. “People almost trivialize it.”
But maybe something else is at work: the triple bond Z, for example, can add stability and stiffness to DNA and may affect some of its other physical properties. These changes could bring benefits in addition to hiding from bacterial defenses and could make such modifications more significant.
After all, no one really knows how many viruses could play with their DNA like this. “Standard [genome sequencing] methods for searching for biodiversity in nature would fail to find them, ”he said Steven Benner, a chemist from the Florida Foundation for Applied Molecular Evolution, who synthesized several artificial base pairs, “because we search in a way that assumes a common biochemistry that is not present.”
These types of overlooked substitutions can occur in more than a virus. “Maybe we missed some of this in the bacterial world, didn’t we?” he said Chuan He, a chemical biologist from the University of Chicago.
Synthetic biology has (again) shown that this is possible. For years, Marlière’s team has been evolving E. coli which use a modified base instead of T nucleotides. Huimin Zhao, a chemist at the University of Illinois, Urbana-Champaign and leader of some recent work on the Z genome, is trying to get E. coli and potentially other cells that include Z as viruses do.
Romesberg thinks these findings could raise questions about modifications to bacterial DNA that were thought to be epigenetic — that is, changes made to nucleotides after DNA synthesis, usually to affect gene expression. Replacing Z, he said, “shows that things you might have thought were epigenetic might not be.”
“I think people should look under the stones that were thought to be understood,” he added. “That’s where the surprises come from.”
But there’s also plenty of room for surprises in less well-studied places, because “we can’t cultivate most of the Earth’s microbes,” he said Carol Cleland, a philosopher of science from the University of Colorado, Boulder. “Are there other things we just can’t recognize?”
Marlière wonders, for example, whether scientists can one day come across multiple types of base modifications in a single genome. Or they might find a change in the molecular backbone of DNA, in which case “it would no longer be DNA,” he said. “It would be something else.”
We need to “stop taking the components of molecular biology the way we take them for granted,” Freeland said. “Purely because our instruments got better and we looked heavier, everything we thought was standard and universal simply falls away.”
An original story reprinted with permission Quanta Magazine,, editorially independent publication Simons Foundation whose mission is to improve the understanding of science in public by covering the development of research and trends in mathematics and the physical and life sciences.
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