Adaptive mutation mechanism may explain some forms of antibiotic resistance

RNA molecule
This is a computer graphic of an RNA molecule. Credit: Richard Feldmann/Wikipedia

Evolutionary theory says mutations are blind and occur randomly. But in the phenomenon of adaptive mutation, cells can peek under the blindfold, increasing their mutation rate in response to stress.

Scientists at Winship Cancer Institute, Emory University have observed that an apparent "back channel" for genetic information called retromutagenesis can encourage adaptive mutation to take place in bacteria.

The results are scheduled for publication in PLOS Genetics on Tuesday, August 25.

"This mechanism may explain how bacteria develop resistance to some types of antibiotics under selective pressure, as well as how in enable their growth or resistance to chemotherapy drugs," says senior author Paul Doetsch, PhD.

Doetsch is professor of biochemistry, radiation oncology and hematology and medical oncology at Emory University School of Medicine and associate director of basic research at Winship Cancer Institute. The first author of the paper is recently graduated Genetics and Molecular Biology graduate student Jordan Morreal, PhD.

Retromutagenesis resolves the puzzle: if cells aren't growing because they're under stress, which means their DNA isn't being copied, how do the new mutants appear?

The answer: a mutation appears in the RNA first.

The mutation in the RNA results in a protein with augmented function that helps the cells grow, giving them a chance to replicate their DNA and for subsequent DNA mutations to exert their effects.

In the PLOS Genetics paper, scientists led by Doetsch and colleague Bernard Weiss, MD, provide evidence that retromutagenesis is occurring in E. coli bacteria forced to grow on the sugar lactose as their only source of energy.

The bacterial strain tested had a disabling mutation in a gene that, if functional, would allow the cells to use lactose. When exposed to high levels of nitrous acid, a DNA-damaging agent, mutations appeared in the bacteria and some of the bacteria could grow. By analyzing where exactly on the DNA the mutations occurred, the scientists concluded that retromutagenesis was contributing to bacterial growth.

"Most of the previous experiments on adaptive mutation have attempted to rule out growth of the parent during selection, which is almost impossible to do with the necessary rigor... Instead of measuring overall DNA replication via cellular growth in the parental population during selection as in previously published experiments, we are able to gauge DNA replication specifically in the revertants via NTS [non-transcribed strand] mutations. Low frequency of NTS mutations found after direct selection indicates there was little DNA synthesis before gene expression and strongly supports the model of retromutagenesis," the authors write.

The authors note that retromutagenesis may explain previous observations of bacteria developing resistance to the antibiotic ciprofloxacin, as well as mutations in the human p53 Ras oncogene, seen in many forms of cancer.


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JVK
Aug 25, 2015
The mutation in the RNA results in a protein with augmented function that helps the cells grow, giving them a chance to replicate their DNA and for subsequent DNA mutations to exert their effects.


That's why people suffer and/or die of virus-driven pathologies. Pseudoscientists believe in theories about beneficial mutations because they aren't taught the facts about RNA-mediated events, which link thermodynamic cycles of protein biosynthesis and degradation from ecological variation to nutrient-dependent ecological adaptations via the physiology of reproduction in all living genera.

Viral microRNAs perturb protein folding. Nutrient-dependent microRNAs help to ensure the stability of organized genomes that links viruses from entropic elasticity to genomic entropy. Mayo clinic researchers are on the verge of telling all evolutionary theorists that they are biologically uninformed science idiots, but they obviously are having trouble trying to say it politely.

JVK
Aug 25, 2015
See for comparison:

https://www.youtu...TLOGZ40U

The Mayo Clinic appears to be making rapid advances based on what is known about links from viruses to pathology, which typically is biophysically constrained by nutrient-dependent microRNAs during thermodynamic cycles of RNA-mediated protein biosynthesis and degradation.

The cycles link the conserved molecular mechanisms of RNA-mediated gene duplication and amino acid substitutions to cell type differentiation in all cell types in all individuals of all living genera via the physiology of reproduction.

The physiology of reproduction links the epigenetic landscape to the physical landscape of DNA via metabolic networks and genetic networks that link nutritional epigenetics to pharmacogenomics via changes in the microRNA/messenger RNA balance that alter RNA-mediated protein folding.

Aug 25, 2015
The Mayo Clinic study has nothing to do with viruses!

http://newsnetwor...ossible/

In your bizarre world someone gets lung cancer from a virus and not from a lifetime of smoking.

JVK
Aug 26, 2015
http://journals.p....1005477

Concluding sentence:

"Retromutagenesis is a transcription-mediated process of adaptive mutation that requires a damaged gene to be expressed before it can be replicated. In light of previous evidence, it is probably one of several mechanisms by which cells can undergo directed selection in the absence of apparent growth."

Virus-driven mutations are eliminated by RNA-mediated gene duplication and RNA-mediated amino acid substitutions that link the epigenetic landscape to the physical landscape of DNA in all living genera via DNA repair mechanisms until the accumulation of viral microRNAs overwhelms the ability of nutrient-dependent microRNAs to repair DNA.

That's why some people get lung cancer from smoking, which suppresses the innate immune system's RNA-mediated DNA repair mechanisms. If the people at the Mayo Clinic do not already know this, they will learn.

JVK
Aug 26, 2015
It is great to see that these researchers are extending an accurate representation of biologically-based cause and effect to what has already been presented in this video from the Mayo Clinic. I think this will put an end to the pseudoscientific nonsense about beneficial mutations that has been touted by neo-Darwinian theorists who never learned how nutrient-dependent RNA-mediated cell type differentiation occurs.

https://www.youtu...G_9EEeeA

Excerpt from my invited review of nutritional epigenetics:
"This atoms to ecosystems model of ecological adaptations links nutrient-dependent epigenetic effects on base pairs and amino acid substitutions to pheromone-controlled changes in the microRNA / messenger RNA balance and chromosomal rearrangements. The nutrient-dependent pheromone-controlled changes are required for the thermodynamic regulation of intracellular signaling, which enables biophysically constrained nutrient-dependent protein folding..."

Aug 26, 2015
Virus-driven mutations are eliminated by RNA-mediated gene duplication


Gene duplication merely makes copies of genes. It has nothing to do with eliminating other mutations.

the ability of nutrient-dependent microRNAs to repair DNA


miRNAs bind to specific mRNAs and alter the translation process. They are not involved in the DNA repair process.

There's a lovely picture on this page that succinctly describes them because I know reading is difficult for you:

https://en.wikipe...MicroRNA

JVK
Aug 26, 2015
I wrote: Virus-driven mutations are eliminated by RNA-mediated gene duplication and RNA-mediated amino acid substitutions

Andrew Jones clipped what I wrote and changed the context:
Virus-driven mutations are eliminated by RNA-mediated gene duplication


His tactics are those of other anonymous fools who know nothing about cell type differentiation and do not want others to learn what is known about it to serious scientists.

https://www.googl...mediated

Duplicate genes that are not required for ecological adaptation acquire mutations and become pseudogenes if they are not eliminated from organized genomes in their entirety. That is what's been learned in the context of the octopus genome sequencing, which fits into my model of RNA-mediated cell type differentiation precisely the way I detailed it and exemplified it across species.

http://www.ncbi.n...24693353

JVK
Aug 26, 2015
miRNAs bind to specific mRNAs and alter the translation process. They are not involved in the DNA repair process.
--Andrew Jones

How is DNA repaired in the absence of nutrient-dependent microRNAs?

Note: Every claim that Andrew Jones (aka anonymous_9001) has ever made attests to what does not happen.

He will not tell us anything about how RNA-mediated cell type differentiation occurs in the context of amino acid substitutions that stabilize the organized genomes of all living genera because he is a biologically uninformed science idiot.

JVK
Aug 26, 2015
http://medicalxpr...tml#nRlv

Excerpt: "Many factors, including sunlight, even chemotherapy, can cause DNA mutations. Mutations can even occur in the normal process of a cell multiplying, as cells do commonly in areas such as the skin and gastrointestinal tract, and tend to increase with aging. Cancer itself can cause additional mutations as it morphs to try to escape whatever treatment is being used against it. In fact, DNA repair likely is a constant in the body that works well most of the time. "That is why understanding DNA damage response is so important," said Yan."

Again,
How is DNA repaired in the absence of nutrient-dependent microRNAs?

If you don't understand why that question must be answered, it's because you are a biologically uninformed science idiot who has been taught to believe in pseudoscientific nonsense about mutations and evolution.

JVK
Aug 26, 2015
http://www.nature...549.html

Excerpt: Furthermore, adjusting for oscillators using the characterization provided by Oscope should increase the power to investigate other signals associated with differentiation and/or subpopulations15.

In other words, everything you think you know about mutations and evolution has been or will be replaced by what serious scientists have already learned or will learn about how ecological variation leads to nutrient-dependent ecological adaptations during life history transitions of species from microbes to man.

See also: Molecular Vibration-Sensing Component in Human Olfaction http://dx.doi.org....0055780
Reported June 3, 2014 as: Proteins 'ring like bells': Quantum mechanics and biochemical reactions http://www.scienc...2424.htm

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