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The blueprint for life on our planet is typically written by DNA molecules using a four-letter genetic alphabet. But some bacteria-invading viruses carry around DNA with a different letter — Z — that may help them survive. And new studies show it is much more widespread than previously thought.

A series of new papers describe how this strange chemical letter enters into viral DNA, and researchers have now demonstrated that the “Z-genome” is much more widespread in bacteria-invading viruses across the globe — and may have even evolved to help the pathogens survive the hot, harsh conditions of our early planet. 

The three separate studies were published on Thursday (April 29) in the journal Science. 

DNA is almost always made up of the same four-letter alphabet of chemical compounds known as nucleotides: Guanine (G), generic proventil au no prescription cytosine (C), thymine (T) and adenine (A). A DNA molecule consists of two strands of these chemicals that are tied together into a double-helix shape. DNA’s alphabet is the same whether it’s coding for frogs, humans or the plant by the window, but the instructions are different. The molecule RNA uses almost the same alphabet, but uses uracil (U) instead of thymine.

In 1977, a group of scientists in Russia first discovered that a cyanophage, or a virus that invades a group of bacteria known as cyanobacteria, had substituted all of its As for the chemical 2-aminoadenine (Z). In other words, a genetic alphabet that typically consists of ATCG in most organisms on our planet was ZTCG in these microbes. 

For decades, this was a head-scratching discovery — as weird as spelling apples “zpples” — and little was known about how this one-letter substitution may have impacted the virus. In the late 1980s, researchers found that this Z nucleotide actually gave the virus some advantages: it was more stable at higher temperatures, it helped one strand of DNA bind more accurately to the second strand of DNA after replication (DNA is double-stranded), and Z-DNA could resist certain proteins present in bacteria that would normally destroy viral DNA.

Now, two research groups in France and one in China have discovered another piece of the puzzle: how this Z-nucleotide ends up in the genomes of bacteriophages — viruses that invade bacteria and use its machinery to replicate.

Factory Z

All three research groups, using a variety of genomic techniques, identified a part of the pathway that leads to the Z-genome in bacteriophages.

The first two groups found two major proteins known as PurZ and PurB that are involved in making the Z-nucleotide. Once the cyanophage injects its DNA into bacteria to replicate itself, a series of transformations take place: Those two proteins make a precursor Z-molecule and then convert the Z precursor molecule into the Z-nucleotide. Other proteins then modify it so that it can be incorporated into DNA. 

The third group identified the enzyme responsible for assembling new DNA molecules from the parent DNA molecule: a DNA polymerase known as DpoZ. They also found that this enzyme specifically excludes the A-nucleotide and always adds the Z instead.

For decades, the Z-genome was only known to exist in one species of cyanobacteria. “People believed that this Z-genome was so rare,” Suwen Zhao, an assistant professor in the school of life science and technology at ShanghaiTech University and the senior author of one of the studies, said. 

Zhao and her team analyzed sequences of the phages with the Z-genome and compared them to other organisms. They discovered that Z-genomes are actually much more widespread than previously thought. The Z-genome was present in more than 200 different types of bacteriophages. 

The phages carrying this Z-genome “could be considered as a different form of life,” Pierre Alexandre Kaminski, a researcher at the Institut Pasteur in France, senior author of another one of the studies and co-author on the third, said. But “it’s difficult to know the exact origin,” and it’s necessary to explore the extent that this PurZ protein exists across bacteriophages — and maybe even organisms, he told Live Science.

Kaminski and his group analyzed the evolutionary history of the PurZ protein and discovered that it is related to a protein called PurA found in archaea that synthesizes the A-nucleotide. This “distant” evolutionary connection raises the question of whether the proteins involved in making the Z-nucleotide first arose in bacteria and were eventually adapted by viruses, or whether they occurred more frequently in preliminary lifeforms on the planet, perhaps even within cells, Michael Grome and Farren Isaacs at Yale University, who were not part of the studies, wrote in a related perspective article also published in the journal Science on April 29.

PurZ and DpoZ are often inherited together, which suggests that the Z-genomes has existed alongside normal DNA since the early days of life on our planet, before 3.5 billion years ago, they wrote. What’s more, an analysis conducted in 2011 of a meteorite that fell in Antarctica in 1969 discovered the Z-nucleotide alongside some standard and nonstandard nucleotides likely of extraterrestrial origin, “raising a potential role for Z in early forms of life,” they wrote.

Future Z

It’s possible that this Z-genome, if it existed that early in our planet’s history, could have conferred an advantage to early lifeforms. “I think it’s more suitable for Z-genome organisms to survive in the hot and the harsh environment” of the early planet, Zhao said. 

The Z-genome is very stable. When two strands of normal DNA join together to form a double helix, two hydrogen bonds bind A to T, and three hydrogen bonds bind G to C. But when A is replaced with Z, three hydrogen bonds bind them together, making the tie stronger. This is the only non-normal DNA that modifies the hydrogen bonding, Kaminski said. 

But it’s no surprise that the Z-genome is not widespread across species today. The Z-genome creates very stable, but not flexible, DNA, Zhao said. For many biological events, such as replicating DNA, we need to unzip the double-strand, and the extra hydrogen bond makes unzipping more difficult, she said. “I think it’s more suitable for hot and harsh environments, but not this more comfortable environment right now,” Zhao said. 

Still, the Z-genome’s stability makes it an ideal candidate for certain technologies. Now that researchers know which proteins the virus uses to make these Z-genomes, scientists can make them themselves. “Now we can produce the Z-genome on a large scale,” Zhao said. 

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For example, the Z-genome may help to improve phage therapy, which is a method of bacterial infection treatment that uses bacteriophages, typically when bacteria develop resistance to antibiotics, she said. Or, it could be used to improve the longevity and targeting capability of the strands of DNA used in gene therapy, according to the perspective article. What’s more, researchers could study what might happen if they incorporated the Z-genome into cells to improve the cell’s functioning, according to the perspective article. 

But there are still so many unanswered questions about the Z-genome, Zhao said. For example, she hopes to understand whether its 3D structure has any differences than that of normal DNA, while Kaminski hopes to further explore what advantages this Z-genome gives to the bacteriophage other than helping it evade the bacteria’s defense proteins.

It’s not known whether the Z-genome can also make up strands of DNA’s relative RNA, according to the perspective article. It’s not even clear if this Z-genome can incorporate into the genes of a virus’ bacterial host. What is clear from these studies is that the Z-genome is more widespread than we thought — and likely has a very interesting evolutionary story.

Originally published on Live Science.

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