Molecular alternatives to DNA, RNA offer new insight into life's origins

April 19, 2012, Arizona State University

Living systems owe their existence to a pair of information-carrying molecules: DNA and RNA. These fundamental chemical forms possess two features essential for life: they display heredity—meaning they can encode and pass on genetic information, and they can adapt over time, through processes of Darwinian evolution.

A long-debated question is whether and evolution could be performed by molecules other than DNA and .

John Chaput, a researcher at ASU's Biodesign Institute, who recently published an article in Nature Chemistry describing the evolution of threose nucleic acids, joined a multidisciplinary team of scientists from England, Belgium and Denmark to extend these properties to other so-called Xenonucleic acids or XNA's.

The group demonstrates for the first time that six of these unnatural nucleic acid polymers are capable of sharing information with DNA. One of these XNAs, a molecule referred to as anhydrohexitol nucleic acid or HNA was capable of undergoing directed evolution and folding into biologically useful forms.

Their results appear in the current issue of Science.

The work sheds new light on questions concerning the origins of life and provides a range of practical applications for molecular medicine that were not previously available.

Nucleic acid aptamers, which have been engineered through in vitro selection to bind with various molecules, act in a manner similar to antibodies—latching onto their targets with high affinity and specificity. "This could be great for building new types of diagnostics and new types of biosensors," Chaput says, pointing out that XNAs are heartier molecules, not recognized by the natural enzymes that tend to degrade DNA and RNA. New therapeutics may also arise from experimental Xenobiology.

Both RNA and DNA embed data in their sequences of four nucleotides—information vital for conferring hereditary traits and for supplying the coded recipe essential for building proteins from the 20 naturally occurring amino acids. Exactly how (and when) this system got its start however, remains one of the most intriguing and hotly contested areas of biology.

According to one hypothesis, the simpler RNA molecule preceded DNA as the original informational conduit. The RNA world hypothesis proposes that the earliest examples of life were based on RNA and simple proteins. Because of RNA's great versatility—it is not only capable of carrying genetic information but also of catalyzing chemical reactions like an enzyme—it is believed by many to have supported pre-cellular life.

Nevertheless, the spontaneous arrival of RNA through a sequence of purely random mixing events of primitive chemicals was at the very least, an unlikely occurrence. "This is a big question," Chaput says. "If the RNA world existed, how did it come into existence? Was it spontaneously produced, or was it the product of something that was even simpler than RNA?"

This pre-RNA world hypothesis has been gaining ground, largely through investigations into XNAs, which provide plausible alternatives to the current biological regime and could have acted as chemical stepping-stones to the eventual emergence of life. The current research strengthens the case that something like this may have taken place.

Threose nucleic acid or TNA for example, is one candidate for this critical intermediary role. "TNA does some interesting things," Chaput says, noting the molecule's capacity to bind with RNA through antiparallel Watson-Crick base pairing. "This property provides a model for how XNAs could have transferred information from the pre-RNA world to the RNA world."

Nucleic acid molecules, including DNA and RNA consist of 3 chemical components: a sugar group, a triphosphate backbone and combinations of the four nucleic acids. By tinkering with these structural elements, researchers can engineer XNA molecules with unique properties. However, in order for any of these exotic molecules to have acted as a precursor to RNA in the pre-biotic epoch, they would need to have been able to transfer and recover their information from RNA. To do this, specialized enzymes, known as polymerases are required.

Nature has made DNA and RNA polymerases, capable of reading, transcribing and reverse transcribing normal nucleic acid sequences. For XNA molecules, however; no naturally occurring polymerases exist. So the group, led by Phil Holliger at the MRC in England, painstakingly evolved synthetic polymerases that could copy DNA into XNA and other polymerases that could copy XNA back into DNA. In the end, polymerases were discovered that transcribe and reverse-transcribe six different genetic systems: HNA, CeNA, LNA, ANA, FANA and TNA. The experiments demonstrated that these unnatural DNA sequences could be rendered into various XNAs when the polymerases were fed the appropriate XNA substrates.

Using these enzymes as tools for molecular evolution, the team evolved the first example of an HNA aptamer through iterative rounds of selection and amplification. Starting from a large pool of DNA sequences, a synthetic polymerase was used to copy the DNA library into HNA. The pool of HNA molecules was then incubated with an arbitrary target. The small fraction of that bound the target were separated from the unbound pool, reverse transcribed back into with a second synthetic enzyme and amplified by PCR. After many repeated rounds, HNAs were generated that bound HIV trans-activating response RNA (TAR) and hen egg lysosome (HEL), which were used as binding targets.) "This is a synthetic Darwinian process," Chaput says. "The same thing happens inside our cells, but this is done in vitro."

The method for producing XNA polymerases draws on the path-breaking work of Holliger, one of the lead authors of the current study. The elegant technique uses cell-like synthetic compartments of water/oil emulsion to conduct directed evolution of enzymes, particularly polymerases. By isolating self-replication reactions from each other, the process greatly improves the accuracy and efficiency of polymerase evolution and replication. "What nobody had really done before," Chaput says, "is to take those technologies and apply them to unnatural nucleic acids. "

Chaput also underlines the importance of an international collaboration for carrying out this type of research, particularly for the laborious effort of assembling the triphosphate substrates needed for each of the 6 XNA systems used in the study:

"What happened here is that a community of scientists came together and organized around this idea that we could find polymerases that could be used to open up biology to unnatural polymers. It would have been a tour de force for any lab to try to synthesize all the triphosphates, as none of these reagents are commercially available."

The study advances the case for a pre-RNA world, while revealing a new class of XNA aptamers capable of fulfilling myriad useful roles. Although many questions surrounding the origins of life persist, Chaput is optimistic that solutions are coming into view: "Further down the road, through research like this, I think we'll have enough information to begin to put the pieces of the puzzle together."

Explore further: Simpler times: Did an earlier genetic molecule predate DNA and RNA?

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3 / 5 (1) Apr 19, 2012
The problem with these RNA analogues are, besides the parsimony problem of not being necessary, that they are most often stabler than RNA. Which means the evolution to RNA, and back to the stabler DNA, seems problematic with its lack of selection pressure.
4.2 / 5 (6) Apr 19, 2012
@ A2G/okyeasno: You both seem unfamiliar with evolution, which is known to insert the information in the environment into the genome.

okyesno, you seem especially unfamiliar with the fact that the genome of a population contains _less_ information than unordered non-gene DNA. You should look up Kolomogorov complexity, which measures this information. Evolution is a process where Shannon information channeled from the environment is used to fix genes by lowering the DNA information content.
4.4 / 5 (7) Apr 19, 2012
DNA contains information, but genetic DNA contains less. As I say, look up KC. Algorithmic KC is the basis for coding real world computers.

And you confuse the genetic code with gene alleles and their expression, the code distinguishes between amino acids but doesn't tell how they are selected and inserted or deleted from the genome. It is known that evolution does that. The genetic code on the other hand is part of the cellular machinery which is inherited at cell division. So the use is completely unintelligent - its chemistry, in the same way that there is no intelligence involved in telling a light ray to go straight - its physics.

4.5 / 5 (8) Apr 19, 2012
To short circuit the next entirely irrelevant claim to biology -you still have to look up KC information and what it means before you try to discuss it - you have it completely backwards.

So: naturally the cellular machinery, inherited for so many billion years, have evolved over time. That is why the process can be described as the process from chemical to biological evolution, which the article is about.

Finally, you just revealed that you don't care for the mind of scientists or science results. Which puts the question why you are here if you really don't care about these results, except for trolling.
4.2 / 5 (5) Apr 19, 2012
DNA contains coded information. In the real world (not minds of scientists), both developing of a code and using the code to transmit a message requires intelligence. Seems very implausible that the only exception to this rule would be life itself.

2 words- selective reactivity. Chemistry guides how things react. That is the simplest form of information.
3 / 5 (2) Apr 19, 2012
If you look at an unknown book in a shop, you start to wonder who wrote it.

well, god did it? i can't think of any other mechanism...
1 / 5 (4) Apr 19, 2012
So, this is one hypothesis. What are the other possible explanations (including design...that cannot just be assumed away)? It would be beneficial to see a comparison of them side-by-side, along with proposed experiments and models that would scientifically help us infer to the best explanation. One challenge that we have to watch out for is that "intelligent design" is relied upon by the experimenters in all abiogenetic experiments done to date to stack the deck with respect to initial conditions. This makes it difficult to truly demonstrate undirected processes, random mutation and natural selection.
1 / 5 (1) Apr 20, 2012
Evolution is a process where Shannon information channeled from the environment is used to fix genes by lowering the DNA information content.

Lowering the amount of information available to deal with problems means evolution isn't an advancement, but a degradation in and of itself.

You are also simply assuming the environment affects genetic reproduction, but I've yet to see that proved anywhere, or how it would ever know. How would your genetics ever know the difference between rain and a spray hose? How would it ever pass that info on to it's offspring?

Chemistry is also defined, it does not vary. How you can go from a direct relationship such as 2H2 02 = 2H20 to variable chromosomes is not defined either. Chemistry doesn't allow random chaos.
4.4 / 5 (7) Apr 20, 2012
Lowering the amount of information available to deal with problems means evolution isn't an advancement, but a degradation in and of itself.

I think this is not right. There are lots of simpler animals and microbes (even rice!) with much bigger DNA genome than humans. Are we 'degradation' compared to them? Also word 'advancement' is not appropriate when talking evolution.
1 / 5 (1) Apr 21, 2012
over-rated research and supposed implications
1 / 5 (1) Apr 23, 2012
I think this is not right. There are lots of simpler animals and microbes (even rice!) with much bigger DNA genome than humans. Are we 'degradation' compared to them?

You tell me. If bigger DNA implies increased complexity, then yes we are a degradation, and they are not so simple. We have lost potential functionality and capability in comparison. Microbes are far better than us at survival. So why would any microbe ever evolve to something less efficient overall?

not rated yet Apr 23, 2012
@okyesno Seems very implausible that the only exception to this rule would be life itself.
As if you ever studied probability and statistics LOL!
If you look at an unknown book in a shop, you start to wonder who wrote it.
well, god did it? i can't think of any other mechanism...
Fundies like okyesno should ponder why their god itself is an ATHEIST. Doesn't that make atheism the most enlightened school of thought?

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