Multiple silent mutations greatly impact protein translation, study finds

This is a visual readout of the varied effects of silent mutations in the bacteria, Salmonella enterica. Credit: Fabienne Chevance

So-called silent DNA mutations earned their title because, according to the fundamental rules of biology, they should be inconsequential. Reported on June 5 in PLOS Genetics online, University of Utah researchers experimentally proved there are frequent exceptions to the rule. The work was conducted in the bacteria, Salmonella enterica, used to study basic biological mechanisms that are often conserved in humans.

"In this post-genomic era, where a patient's DNA sequence can be used to diagnose predisposition to diseases, silent mutations are usually ignored," said senior author Kelly T. Hughes, professor of biology at the University of Utah. "Our data argue that they shouldn't be."

The definition of a silent mutation rests on a fundamental principle in biology. DNA is transcribed into RNA, and RNA is translated into protein. Using an analogy, DNA are letters, and when grouped into three-letter words, they form a code that specifies which protein will be made. A silent mutation is similar to a "c" to "k" change in "the cat ran" and "the kat ran." Despite the alternate spelling, the meaning is the same.

Because Hughes had assumed the dogma on silent mutations to be true, he nearly lost the chance to make an important discovery. Twenty years prior, he had dismissed experimental results implicating a silent mutation as the cause of a severe defect in bacteria.

"We thought there was some other mutation somewhere else that we couldn't find," remarked Hughes. "We didn't realize at the time that we were throwing away gold."

In the years following, evidence started to emerge indicating that silent changes could have serious consequences to bacteria and animals. But the cases were isolated, and it remained to be determined whether they were part of a larger phenomenon.

In light of the new data, Hughes decided to pursue his finding from years ago, but on a broader scale. He developed an assay to test the effects of all possible silent mutations on in bacteria. The beauty of the system is that it eliminates many of the variables that could be introduced at intermediate steps in the process, meaning any effect on translation should directly link back to the change in DNA.

"I didn't think it would work," said research assistant professor and first author Fabienne Chevance. "I didn't imagine that a single base pair change could have as big of an effect as we saw."

The assay showed that an unexpected one-third of silent mutations caused protein translation to slow down, in some cases decreasing the speed by as much as five-fold. The scientists surmise that just as the alternate spelling in "the kat ran" might cause a reader to hesitate, certain silent mutations causes the ribosomal machinery that carries out translation to balk.

Silent mutations weren't the only types of DNA changes to effect translation efficiency. It turns out that for the words in the sentence—called codons—what your neighbors are matters. For example, "the cat ran" could be read faster than "the ran cat." The phenomenon, dubbed "codon context," changed the speed of translation by up to 30-fold.

The implications are that similar changes within any protein coding region could alter the amount of protein made, ultimately impacting the fitness of the organism.

The conclusions fit well with observations from population biologists, who found that specific silent mutations and codon contexts are statistically underrepresented in protein coding regions in many organisms, suggesting those codes could be detrimental. The results from Chevance and Hughes explain the biology behind the statistics and represent the first systematic validation of the phenomena in a living organism in real time.

"We've been able to experimentally prove what population geneticists have believed for decades," said Hughes. "Every DNA base can matter."

More information: The paper titled, "The effects of codon context on in vivo translation speed" by Fabienne F.V. Chevance, Soazig Le Guyon, and Kelly T. Hughes will be published online in the journal PLOS Genetics on June 5, 2014 www.plosgenetics.org/doi/pgen.1004392

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JVK
1 / 5 (3) Jun 05, 2014
Re: "We've been able to experimentally prove what population geneticists have believed for decades," said Hughes. "Every DNA base can matter."

They proved that ecological variation in the availability of nutrients cause changes in base pairs, which result in amino acid substitutions. The substitutions differentiate cell types in species from microbes to man.

Cell type differentiation is species-specific and controlled by the metabolism of nutrients to pheromones. Pheromones control the physiology of reproduction, which means they just proved the theory of mutation-initiated natural selection, which supposedly led to evolution of biodiversity, is pseudoscientific nonsense.

Ecological variation leads to ecological adaptations manifested in the morphological and behavioral phenotypes of species from microbes to man via conserved molecular mechanisms.

Only population geneticists could still believe that biodiversity results from mutations, natural selection, and evolution.
JVK
1 / 5 (3) Jun 05, 2014
In the journal article, I am struck by the absurdity of their proposal that base pair changes automagically link messenger RNA to mutation-driven cell-type differentiation.

What's worse is their mention of attenuated viral virulence when it is known that glucose dependent amino acid substitutions cause seasonal differences in the human influenza virus, which is why a new vaccination is required each year. http://www.scienc...abstract

Does anyone else know why population geneticists have not grasped the basic principles of biology and levels of biological organization that are required to link sensory input to cell type differentiation that they think is mutation-driven?

Is the problem with their understanding of physics, chemistry, molecular biology, or is it a problem that results from their belief in the pseudoscientific nonsense of neo-Darwinism and the invention of evolutionary theory in the early part of the last century?
Captain Stumpy
5 / 5 (3) Jun 06, 2014
Only population geneticists could still believe that biodiversity results from mutations, natural selection, and evolution
@jk
and only you could believe that your model supports biodiversity but does not support evolution
you are too ignorant (actually, this would be stupid at this point as it has been repeatedly pointed out to you) to comprehend that your model creates mutations, which only supports the above article

you just don't quit... the perfect acolyte. ignore empirical data, believe in something so strongly that nothing will change your mind, shout it to everyone regardless of how stupid you look
Ecological variation leads to ecological adaptations manifested in the morphological and behavioral phenotypes of species from microbes to man via conserved molecular mechanisms
via mutations
your model proves this, jk
your model causes mutations
that's why your model is already a part of evolution
that's why your model supports mutation driven evolution & biodiversity
russell_russell
3 / 5 (1) Jun 09, 2014
The source of mutation is damage. How damage occurs is irrelevant. The repair is what counts.

(No living cell is damage-free)

Does a 'perfect' repair (replacement) exist? No. You can not replace the original with another original because by definition of an original there exists only one... original.

So what is the difference between the best possible repair or replacement to the original?
The difference is labeled evolution, learning and memory. For starters.

Congratulations goes out to this research, researchers, and all related research not daunted, thwarted, or persuaded from dogma and/or 'fundamentals'.
JVK
1 / 5 (2) Jun 09, 2014
The difference between the best possible repair or a replacement to the original should be labeled "ecological adaptation" since it is nutrient-dependent and pheromone-controlled in the context of cell-type differentiation.

If you label the difference "evolution" you invite anonymous fools and idiot minions of biology teachers like PZ Myers to claim that mutations and natural selection contribute to the evolution of biophysically constrained biodiversity.

These fools and idiots show up each time intelligent discussion of conserved molecular mechanisms that enable ecological variation to result in ecological adaptations might otherwise contribute to a better understanding of what goes wrong when mutations cause diseases and disorders.

See for example of the potential for intelligent discussion: http://medicalxpr...cer.html
russell_russell
not rated yet Jun 09, 2014
But no one has credibly shown how molecules learned to think. - Chopra


How unfortunate for Chopra.

http://ac.els-cdn...c49b7637

You have made room for epimutation. A paradigm shift. Do not expect anyone to understand you.

Just as I do not expect Chopra to believe researchers the world over have shown credibly how molecules learn to think.

I will meet you half way and label the best possible repair or replacement to the original (for memory and learning, and not in the context of cell-type differentiation) is epimutation.

In other words a rose is a rose in any language spoken and any spoken language uses the different sounds (mechanical vibrations) as an expression for the same object: a rose.

What sound is for a rose spoken in any language, that is for DNA the DNA methylation.

russell_russell
not rated yet Jun 09, 2014
You will have to digress further. You have a paradigm shift to deal with and as fast as epimutation does occurs in the brain your opponents will not become your proponents overnight.

The potential is there. In the mean time take comfort in that.
And let them 'catch up'. You know, Rome burned in a day.
JVK
1 / 5 (1) Jun 09, 2014
Jon Lieff MD has extended learning and memory in the context of cell type differentiation via alternative splicings of RNA http://jonlieffmd...volution

We did that in our 1996 Hormones and Behavior review.
http://www.hawaii...ion.html

Elekonich extended the model to insects and the life cycle transitions of honeybees

I extended the model across species from microbes to man. http://www.ncbi.n...24693353

The paradigm shift happened and was ignored because evolutionary theorists don't want no stinkin' paradigm shift.

Moshe Szyf: https://www.youtu...mwa2oWyQ

Me: http://youtu.be/DbH_Rj9U524
russell_russell
not rated yet Jun 10, 2014
Jon Lieff's blog is an imaginative mystical tour.
If you demystify all those posted mono- and dialogues of intrigue you are left with one or two sobering paragraphs accounting for all of life known so far.

Imagine a simply formula that finds any or all primes. And no one will argue about 'how many' numbers exist where primes nest.
Now what? And that's not even physical.

Imagine a simply formula that models all life forms - forms extinct, forms now and future forms.
And no one will argue about 'how many' forms of life exist.
Now what?

Nothing short of a never ending journey will satisfy imagination. Reality's roots.
Thks for the links.
JVK
1 / 5 (1) Jun 10, 2014
"Amino acid-sensing neurons (containing fluorescent calcium indicators) can detect nutrient deficiencies in a fruit fly's food."

http://www.the-sc...st102124
Captain Stumpy
not rated yet Jun 10, 2014
I extended the model across species from microbes to man. http://www.ncbi.n...24693353

The paradigm shift happened and was ignored because evolutionary theorists don't want no stinkin' paradigm shift
@jk
it was ignored because your MODEL was already included in Evolution and it is already taken into account via MUTATIONS therefore you are not "shifting paradigms", you are just not able to comprehend your OWN model.
to which I can refer you to many conversations proving that point, as you STILL argue against mutations when your model CAUSES MUTATIONS (see YOUR OWN WORDS here: http://phys.org/n...lts.html when I ask
DOES your model make any changes to the nucleotide sequence of the genome of an organism, virus, or extrachromosomal genetic element?
This is a yes or no answer
(this is the definition of mutation) to which you answered
YES!
--Thanks for asking
russell_russell
not rated yet Jun 11, 2014
Epigenetics can achieve the EXACT same result as a single tweek (SNP).
That is what confuses JVK.
See:
http://medicalxpr...air.html

What occurs more frequency? - alterations to DNA landscape or changes to epigentic landscape from the environment to drive evolution? That can be hotly debated.

Even JVK accepts the label epimutations.
russell_russell
not rated yet Jun 11, 2014
Moving along...
There is a no go theorem in quantum information theory called the no clone theory.
This simply states the xerox of information is forbidden.

That is why evolution occurs at all. The same DNA sequence will give rise to different expressions. And stop believing me. Take as many identical sequences of DNA as you like.
On a superficial scale (less precise measurement) the expressions found will appear identical. If the switches are placed along the same DNA strands theory says the expressions must be identical. That is possible if the strands are isolated from all external factors.

When all external factors are considered the changes from expressions most likely to occur are sourced from the epigenetic landscape changes and not from the variation possible from 'identical' (xerox) strands of DNA that quantum information theory forbids.

Or you can cling to Penrose's abominations of imagination explaining the quantum mind and brain.
Your choice.

JVK
1 / 5 (1) Jun 11, 2014
Anyone who would like to continue to tout mutation-initiated natural selection and the evolution of biodiversity can now frame their pseudoscientific nonsense in the context of this excerpt from my 2013 Review: "In flies, ecological and social niche construction can be linked to molecular-level cause and effect at the cellular and organismal levels via nutrient-dependent changes in mitochondrial tRNA and a nuclear-encoded tRNA synthetase. The enzyme enables attachment of an appropriate amino acid, which facilitates the reaction required for efficient and accurate protein synthesis (Meiklejohn et al., 2013)."
http://www.ncbi.n...24693353

Start with whatever mutation you think links the hormone known as vitamin D to hormone-organized and hormone-activated behaviors associated with serotonin and dopamine in invertebrates and vertebrates and link them to changes in oxytocin for example:
http://medicalxpr...nin.html
JVK
1 / 5 (1) Jun 11, 2014
Epigenetics can achieve the EXACT same result as a single tweek (SNP).
That is what confuses JVK.


What kind of idiot says things like this after I have linked a single epigenetically-effected nutrient-dependent amino acid substitution to mitochondrial interactions and protein biosynthesis and degradation across species from microbes to man via conserved molecular mechanisms that we first detailed in a 1996 review? http://www.ncbi.n.../9047261

Which of the model organisms I used as examples is the one that indicates I am confused about what happened in the mouse to human model of a base pair change and amino acid substitution that led to manifestations in different cell types associated with hair, teeth, sweat glands, and mammary tissue? Who thinks that skin or hair pigmentation represents mutation-initiated changes in cell type differentiation that were naturally selected to result in the evolution of biodiversity? http://www.ncbi.n...24693353
JVK
1 / 5 (1) Jun 11, 2014
"The concept that is extended is the epigenetic tweaking of immense gene networks in 'superorganisms' (Lockett, Kucharski, & Maleszka, 2012) that 'solve problems through the exchange and the selective cancellation and modification of signals (Bear, 2004, p. 330)'. It is now clearer how an environmental drive probably evolved from that of food ingestion in unicellular organisms to that of socialization in insects. It is also clear that, in mammals, food odors and pheromones cause changes in hormones such as LH, which has developmental affects on sexual behavior in nutrient-dependent, reproductively fit individuals across species of vertebrates."

http://www.ncbi.n...24693349

Conclusion: "Olfaction and odor receptors provide a clear evolutionary trail that can be followed from unicellular organisms to insects to humans...."

Correction: The trail links ecological variation to ecological adaptations!
Captain Stumpy
not rated yet Jun 14, 2014
Anyone who would like to continue to tout mutation-initiated natural selection and the evolution of biodiversity can now frame their pseudoscientific nonsense
@jk
but YOU are TOUTING MUTATION INITIATED NATURAL SELECTION WHEN YOU TOUT YOUR MODEL... so you are saying now that you are touting PSEUDOSCIENCE &
pseudoscientific nonsense
ya gotta admit... you really know how to look stupid. no wonder you are considered a pseudoscience crackpot. remember when we talked about mutations?I asked
DOES your model make any changes to the nucleotide sequence of the genome of an organism, virus, or extrachromosomal genetic element?
This is a yes or no answer
to which you answered
YES!
--Thanks for asking
so, drawing from your own words AGAIN...
IF mutations are BAD AND you say yourself that your model causes mutations THEN one can only conclude, per your own words and conclusions, that YOU are an IDIOT TOUTING PSEUDOSCIENTIFIC NONSENSE!

YOUR WORDS again jk, not mine
Captain Stumpy
not rated yet Jun 14, 2014
Which of the model organisms I used as examples is the one that indicates I am confused about what happened in the mouse to human model of a base pair change and amino acid substitution that led to manifestations in different cell types associated with hair, teeth, sweat glands, and mammary tissue? Who thinks that skin or hair pigmentation represents mutation-initiated changes in cell type differentiation that were naturally selected to result in the evolution of biodiversity? http://www.ncbi.n...24693353
@jk
well... YOU think so..... remember when we talked about mutations?I asked
DOES your model make any changes to the nucleotide sequence of the genome of an organism, virus, or extrachromosomal genetic element?
This is a yes or no answer
to which you answered
YES!
--Thanks for asking
so, drawing from your own words AGAIN...
you're an idiot minion touting pseudoscientific nonsense!

this is getting old, jk
you only look worse and worse the more you post
JVK
1 / 5 (1) Jun 14, 2014
http://www.bsd-jo...nt/5/1/8

"...the emergence of sex differences in the brain may be a gradual process that is cemented over the organism's life. Our data provide a new perspective by showing that most sex differences in CpG methylation are dynamic and not the result of acute modifications in response to hormones."

Only an idiot would continue to insist that mutations cause sex differences in cell types or any other differences in cell types in any individual of any species. The differences are nutrient-dependent and pheromone-controlled.

Nutrient-dependent/pheromone-controlled adaptive evolution: a model. http://www.ncbi.n...24693353
Captain Stumpy
not rated yet Jun 14, 2014
Only an idiot would continue to insist
that mutations are BAD when his own model CREATES MUTATIONS and PROVES THE EVOLUTION THEORY while SUPPORTING THE FACT OF DIVERSITY THROUGH MUTATIONS
so, considering that your model CAUSES MUTATIONS
and you are saying that only IDIOTS support mutations in any form (based upon your constant reproach of anyone that supports mutations at all)
then we can conclude that YOU DONT KNOW WHAT YOU ARE TALKING ABOUT
and we can also conclude that you are likely mentally unstable too
JVK
1 / 5 (1) Jun 14, 2014
Horizontal genome transfer as an asexual path to the formation of new species
http://dx.doi.org...ure13291

reported as an example of ecological speciation in http://www.scienc...2201.htm

"The chromosomes are then able to find their suitable partner during meiosis, allowing the plants to stay fertile and a new species is generated."
Captain Stumpy
not rated yet Jun 17, 2014
Nutrient-dependent/pheromone-controlled adaptive evolution: a model
@jk
remember when we talked about mutations?I asked
DOES your model make any changes to the nucleotide sequence of the genome of an organism, virus, or extrachromosomal genetic element?
This is a yes or no answer
(this is the definition of mutation) to which you answered
YES!
--Thanks for asking
and now you say
Only an idiot would continue to insist that mutations cause sex differences in cell types or any other differences in cell types in any individual of any species
then also refer back to your model.
so, LOGICALLY, since your own model creates mutations
YOUR MODEL CANNOT CREATE THE BENEFICIAL DIFFERENCES OR CHANGES that you are suggesting above, because YOUR MODEL CREATES MUTATIONS

so if you are against mutations, why are you not also saying that your own model is incapable of being valid?
there is no place for religion in science, and you are pushing PSEUDOSCIENCE