'Quantum jitters' could form basis of evolution, cancer

March 11, 2015, Duke University
From left to right, the structures of A-, B- and Z-DNA. Credit: Wikipedia

The molecular machines that copy DNA in a living cell are amazingly fast and accurate at pairing up the correct bases—G with C and A with T—into each new double helix.

They work by recognizing the shape of the right base pair combinations, and discarding those—such as a G and a T—that don't fit together correctly. Yet for approximately every 10,000 to 100,000 bases copied, these machines make a mistake that if uncorrected will be immortalized in the genome as a mutation.

For decades, researchers have wondered how these seemingly random errors are made. Some hypothesized that DNA bases can change shapes, transiently morphing into alternative states to trick the replication machinery into incorporating the wrong base pairs into the DNA. But no one has ever caught these tiny shape-shifters in action.

Now, Duke University researchers have witnessed DNA bases making the slightest of changes—shifting a single atom from one spot to another or simply getting rid of it altogether—to temporarily mimic the shape of a different base. These "quantum jitters" are exceedingly rare and only flicker into existence for a thousandth of a second, and yet have far-reaching consequences.

The study, which appears March 12 journal Nature, indicates that these jitters appear at about the same frequency that the DNA copying machinery makes mistakes, which might make them the basis of random genetic changes that drive evolution and diseases like .

"The structure of DNA is inherently tailored to allow mistakes to happen," said Hashim M. Al-Hashimi, Ph.D., a professor of biochemistry at Duke University School of Medicine. "Those mistakes are critical because if we never made them we would never have life as we know it, since we would never evolve. But if we had too many of them, our genes would mutate out of control and we wouldn't survive. These quantum jitters appear to tune the frequency of these spontaneous mutations to just the right level."

DNA's elegant design consists of two long strands twisted around each other like a spiral staircase, with steps made up of four chemicals called bases. Each of these bases contain rings of carbon, along with various configurations of nitrogen, oxygen, and hydrogen. The arrangement of these atoms allow G to pair with C and A to pair with T, like interlocking pieces of a jigsaw puzzle. When DNA is copied, the is careful to only incorporate the perfect fit—known as a Watson and Crick base pairs—and reject any misfits.

Shortly after they discovered the double helix in 1953, Watson and Crick predicted that the four bases might be able to change their shapes so that these mispairs could pass as the real thing. Images of mispairs posing in what appeared to be a Watson-Crick geometry have been captured over the last 10 years and have lent some credence to this idea. But the precise nature of these mispairs and the factors that determine their frequency of occurrence have remained elusive.

Because DNA shape-shifting involves atomic-level movements in larger molecules, it has been impossible to detect by conventional methods. Therefore, Al-Hashimi's team decided to use a sophisticated technique called NMR relaxation dispersion, which he likens to "MRI on steroids," to visualize these fleeting, nearly invisible changes.

Isaac J. Kimsey, a graduate student in the lab, designed a model strand of DNA that contained a G-T mispair. Then he used the NMR technique to track the migration of among the nitrogen and oxygen atoms of the G and T bases. Normally G doesn't pair up very well with T, because they both have hydrogen atoms protruding from their surfaces that clash with each other.

Watson and Crick had originally hypothesized that the bases could nudge hydrogens out of the way to allow mis-matched connections. Aided by the NMR technique, Kimsey provided the first direct evidence for just such an atomic rearrangement in a DNA duplex. He also showed that a similar phenomenon occurs in RNA, the chemical cousin of DNA.

This tiny movement, or "quantum jitter," takes such an enormous amount of energy that bases are successful at accomplishing the feat only once out of every 10,000 or so attempts. Even then, they can only hold their new shape for a very short period of time—50 to 200 microseconds—before the hydrogens pop back into their original position.

The researchers looked back at previous biological studies and found that these rare alternative states appeared in the DNA about as often as the polymerase machinery's copying errors.

"This is a remarkable study that illuminates a fundamental mechanism responsible for the random mutations that drive evolution and contribute to cancer," said Bert Vogelstein, M.D., a cancer researcher at Johns Hopkins University School of Medicine who was not involved in this research.

Kimsey said that a better understanding of how these jitters arise could help in the development of new treatments to fight cancer cells and viruses, for example, forcing them to mutate at a quicker rate so they eventually stop functioning.

"We know that certain carcinogens like 5-bromouridine can make these jitters occur more frequently, said Kimsey, who is lead author of the study. "Therefore, we can use this knowledge to tailor drugs that more rapidly induce cancer cells or viruses to make so many mistakes that they mutate uncontrollably and eventually die."

Explore further: Base-pairing protects DNA from UV damage

More information: "Visualizing Transient Watson-Crick Like Mispairs in DNA and RNA Duplexes," Isaac J. Kimsey, Katja Petzold, Bharathwaj Sathyamoorthy, Zachary W. Stein, and Hashim M. Al-Hashimi. Nature, March 12, 2015. DOI: 10.1038/nature14227

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Eikka
5 / 5 (4) Mar 11, 2015
These quantum jitters appear to tune the frequency of these spontaneous mutations to just the right level.


That's a non-sequitur conclusion.

Rather, it appears that the mechanism of error correction employed in DNA has evolved to limit the frequency of its own mutation to where evolution happens at workable rate.

After all, it takes three base pairs to make a single codon, where flipping any one will not change the resulting code. If the "jitter" rate was higher, four could be used, or the three pairs could be interpreted to carry less information for more redundancy.

It is not given that DNA must work exactly like it does to do its business.
malapropism
5 / 5 (1) Mar 11, 2015
@Eikka
Well, it's true that this is a bit of a leap since at present the similarity between jitter and transcription error rate seems to be only a coincidence or at best a correlation - but it's not really an illogical assumption based on this:
The study ... indicates that these jitters appear at about the same frequency that the DNA copying machinery makes mistakes
Probably a pretty fair bet for their next area of study into this phenomenon, I suspect. I wonder if the change in a single base pair affects the quaternary folding through charge variations in that region of the molecule?
DonGateley
not rated yet Mar 12, 2015
Winging it here so don't hit too hard, but is it conceivable that the jitter process and the correction process could be part of a closed loop where the jitter acts as a sensing set point around which the correction rate can be made to vary? If so, it could be a place where mutation rate comes under the control of cell machinery and gets regulated.

I apologize if that is utter nonsense but occasionally that does happen to my thinking. ;-)
Eikka
5 / 5 (3) Mar 12, 2015
but it's not really an illogical assumption based on this:


It's not illogical, it's just unwarranted.

It's more reasonable to claim that DNA/life has adapted to the background conditions rather than assume the background conditions are "tuned" to fit DNA exactly. Both are valid possibilities, but one is vastly more likely than the other.

Now, if we were to prove that DNA or evolution couldn't work at all if the "jitter" rate was different, that would tip the scales towards the original conclusion, but asserting so without is just begging the question.

JVK
1 / 5 (2) Mar 14, 2015
They appear to have eliminated de Vries definition of "mutation" and the assumptions that population geneticists made about how long the evolution of a new species might take.

DonGateley asks the intelligent question
... is it conceivable that the jitter process and the correction process could be part of a closed loop where the jitter acts as a sensing set point around which the correction rate can be made to vary?


The intelligent answer is: YES! That's what serious scientists would expect to occur in the context of an atoms to ecosystems model of nutrient-dependent cell type differentiation -- if the availability of nutrients biophysically constrained the chemistry of RNA-mediated protein folding, which it obviously does.

That's how ecological variation leads to ecological adaptations in species from microbes to man. It's via RNA-mediated DNA repair and adaptations, which are limited by the food supply and pheromone-controlled reproduction.

JVK
1 / 5 (2) Mar 14, 2015
I wonder if the change in a single base pair affects the quaternary folding through charge variations in that region of the molecule?


I've wondered about that, too. No one ever answered my questions about the sun's biological energy and switches in the quaternary structure and exciton states of cryptophyte light-harvesting proteins. I thought it was obvious that light-induced amino acid substitutions in plants and animals linked their cell type differentiation to the switches via the physiology of reproduction and fixation of the amino acid substitutions.

But the attacks on that apparent fact by biologically uninformed science idiots show up each time I mention anything about it.

Watch for them here (the science idiots, I mean).

Dethe
1 / 5 (2) Mar 15, 2015
Of course that every energy transfer between electrons inside of molecules is mediated with some quantum fluctuation soon or later, but IMO the quantum fluctuations play rather insignificant role in cellular life by itself. Macromolecules like DNA are in wild Brownian motion inside of water solutions, they're colliding, breaking and recombining again - so that the many possible high level mechanisms for mutations can apply here. The Brownian motion is consequence of quantum fluctuations too - we can separate their effects with cooling of biomolecules at the absolute zero. After then the mutations of DNA will be caused with quantum fluctuations only, but - as everyone can imagine - they will be very rare because the molecules will be frozen to bone. This though experiment illustrates the insignificant role of quantum fluctuations for occasional chemical changes of DNA and mutations.
Dethe
1 / 5 (2) Mar 15, 2015
Speaking of random events, the natural background of cosmic rays and gamma radiation will be more significant source of mutations, so that there is no actual reason to consider some role of quantum fluctuations by itself. Apparently the physicists have lotta free time and computer time in their hands and they're drowning in abstract trivialities separated from reality.
JVK
1 / 5 (2) Mar 15, 2015
Thanks again.

This though experiment illustrates the insignificant role of quantum fluctuations for occasional chemical changes of DNA and mutations.


I wonder why theorists do not seem to realize that what they attribute to mutations is pseudoscientific nonsense, which appears to be based on de Vries century-old definition of mutation.

no actual reason to consider some role of quantum fluctuations by itself.


Agreed. Obviously, there is an anti-entropic force that limits entropic elasticity and promotes epistasis. Have you seen any reported peer-reviewed claims that the anti-entropic force is the sun's biological energy, which enables DNA repair of damage caused by cosmic rays?

I submitted an invited review of nutritional epigenetics that linked the balance of viral microRNAs to nutrient-dependent microRNAs and DNA repair that led from epigenesis to epistasis. But it was returned without review. Obviously, most reviewers are theorists.
Steve 200mph Cruiz
4 / 5 (4) Mar 15, 2015
Are you guys freaking retarded? Everyone who actually works in a biological or medical field would think you guys are idiots, maybe there is no conspiracy and your just a bunch of retards, wouldn't that be wild?
JVK
1 / 5 (2) Mar 15, 2015
Everyone who actually works in a biological or medical field would think you guys are idiots


I doubt that, and have two award-winning peer-reviewed publications publications that suggest you are merely an anonymous biologically uninformed science idiot, because I also worked for 39 years as a medical laboratory scientist.

If you have experimental evidence that suggests something besides the viral microRNA / nutrient-dependent microRNA balance, I would be happy to post it to my blog site for comparison to the overwhelming amount of evidence that supports my model of RNA-mediated cell type differentiation via amino acid substitutions.

Welcome to RNA-Mediated http://rna-mediated.com/
Here you will find information that links physics, chemistry, and molecular epigenetics via RNA-mediated events such as the de novo creation of olfactory receptor genes in order to encourage a public discussion of a paradigm shift.

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