Harnessing data from Nature's great evolutionary experiment

DNA

There are 3 billion letters in the human genome, and scientists have endlessly debated how many of them serve a functional purpose. There are those letters that encode genes, our hereditary information, and those that provide instructions about how cells can use the genes. But those sequences are written with a comparative few of the vast number of DNA letters. Scientists have long debated how much of, or even if, the rest of our genome does anything, some going so far as to designate the part not devoted to encoding proteins as "junk DNA."

In work published today in Nature Genetics, researchers at Cold Spring Harbor Laboratory (CSHL) have developed a new to identify which letters in the human are functionally important. Their computer program, called fitCons, harnesses the power of evolution, comparing changes in DNA letters across not just related species, but also between multiple individuals in a single species. The results provide a surprising picture of just how little of our genome has been "conserved" by Nature not only across species over eons of time, but also over the more recent time period during which humans differentiated from one another.

"In model organisms, like yeast or flies, scientists often generate mutations to determine which letters in a DNA sequence are needed for a particular gene to function," explains CSHL Professor Adam Siepel. "We can't do that with humans. But when you think about it, Nature has been doing a similar experiment on a very large scale as species evolve. Mutations occur across the genome at random, but important letters are retained by natural selection, while the rest are free to change with no adverse consequence to the organism."

It was this idea that became the basis of their analysis, but it alone wasn't enough. "Massive research consortia, like the ENCODE Project, have provided the scientific community with a trove of information about genomic function over the last few years," says Siepel. "Other groups have sequenced large numbers of humans and nonhuman primates. For the first time, these big data sets give us both a broad and exceptionally detailed picture of both biochemical activity along the genome and how DNA sequences have changed over time."

Siepel's team began by sorting ENCODE consortium data based on combinations of biochemical markers that indicate the type of activity at each position. "We didn't just use sequence patterns. ENCODE provided us with information about where along the full genome DNA is read and how it is modified with biochemical tags," says Brad Gulko, a Ph.D. student in Computer Science at Cornell University and lead author on the new paper. The combinations of these tags revealed several hundred different classes of sites within the genome each having a potentially different role in genomic activity.

The researchers then turned to their previously developed computational method, called INSIGHT, to analyze how much the sequences in these classes had varied over both short and long periods of evolutionary time. "Usually, this, kind of analysis is done comparing different species - like humans, dogs, and mice - which means researchers are looking at changes that occurred over relatively long time periods," explains Siepel. But the INSIGHT model considers the changes among dozens of human individuals and close relatives, such as the chimpanzee, which provides a picture of evolution over much shorter time frames.

The scientists found that, at most, only about 7% of the letters in the are functionally important. "We were impressed with how low that number is," says Siepel. "Some analyses of the ENCODE data alone have argued that upwards of 80% of the genome is functional, but our evolutionary analysis suggests that isn't the case." He added, "other researchers have estimated that similarly small fractions of the genome have been conserved over long time evolutionary periods, but our analysis indicates that the much larger ENCODE-based estimates can't be explained by gains of new functional sequences on the human lineage. We think most of the sequences designated as 'biochemically active' by ENCODE are probably not evolutionarily important in humans."

According to Siepel, this analysis will allow researchers to isolate functionally important sequences in diseases much more rapidly. Most genome-wide studies implicate massive regions, containing tens of thousands of letters, associated with disease. "Our analysis helps to pinpoint which letters in these sequences are likely to be functional because they are both biochemically active and have been preserved by evolution." says Siepel. "This provides a powerful resource as scientists work to understand the genetic basis of disease."


Explore further

Study suggests a unified model for how DNA is read, offering insight into how genes evolve

More information: "A method for calculating probabilities of fitness consequences for point mutations across the human genome" appears online in Nature Genetics on January 19, 2015. The authors are: Brad Gulko, Melissa Hubisz, Ilan Gronau, and Adam Siepel. The paper can be obtained online at: dx.doi.org/10.1038/ng.3196
Journal information: Nature Genetics

Citation: Harnessing data from Nature's great evolutionary experiment (2015, January 20) retrieved 20 October 2019 from https://phys.org/news/2015-01-harnessing-nature-great-evolutionary.html
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.
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JVK
Jan 20, 2015
Excerpt: "Our analysis helps to pinpoint which letters in these sequences are likely to be functional because they are both biochemically active and have been preserved by evolution."

My comment: Biochemically active sequences that do not perturb protein folding are conserved via fixation of nutrient-dependent amino acid substitutions that stabilize DNA in the organized genomes of species from microbes to man.

Ecological variation that leads to mutations either allows them to be maintained when they are not too detrimental to cell function or they are eliminated when fixation of amino acid substitutions occurs via the nutrient-dependent physiology of pheromone-controlled reproduction.

Gene gain is nutrient-dependent and pheromone-controlled. Gene loss occurs via mutations the perturb protein folding.

http://www.ncbi.n...24693353 Nutrient-dependent/pheromone-controlled adaptive evolution: a model.

See also: http://dx.doi.org.../ng.3142

Jan 20, 2015
Ecological variation that leads to mutations either allows them to be maintained when they are not too detrimental to cell function or they are eliminated ...



You did! You did! You included mutation as part of your understanding of this mechanism!
Man, you are so busted if you continue on with your "mutations are pathogenic" crap...:-)

JVK
Jan 20, 2015
See also: http://medicalxpr...lve.html

Excerpt: According to Siepel, "Our analysis shows that the 'code' for stability is, in large part, written in the DNA, at enhancers and genes alike."

Journal article excerpt: "Production of enhancer RNAs (eRNAs) is also bidirectional and is associated with chromatin modifications or binding of cofactors that are suggestive of enhancer activity (monomethylation of histone H3 at lysine H4 (H3K4me1), p300 binding and acetylation of histone H3 at lysine 27 (H3K27ac))12–14. The widespread existence of eRNAs and uaRNAs raises several important questions regarding how these RNAs are produced and whether they are functional." http://dx.doi.org.../ng.3142

Biologically uniformed science idiots do not understand the difference between RNA-directed DNA methylation that leads to amino acid substitutions and the stability of DNA in organized genomes, and mutations that lead to pathology.

JVK
Jan 20, 2015
If you do not understand anything about chromatin modifications or binding of cofactors that link RNA-mediated events to cell type differentiation in all cells of all individuals of all species, read our 1996 review:

From Fertilization to Adult Sexual Behavior http://www.hawaii...ion.html

Excerpt: "Yet another kind of epigenetic imprinting occurs in species as diverse as yeast, Drosophila, mice, and humans and is based upon small DNA-binding proteins called "chromo domain" proteins, e.g., polycomb. These proteins affect chromatin structure, often in telomeric regions, and thereby affect transcription and silencing of various genes..."

Then read my 2013 review: http://www.ncbi.n...24693353

Only you can stop yourself from being a biologically uninformed science idiot. Rarely does anyone try to save themselves from ongoing displays of anonymous foolishness. Why be a just another fool?

JVK
Jan 20, 2015
See also: New method for analysing RNA sequence data identifies new subtypes of cells
http://phys.org/n...tml#nRlv

Excerpt: "If all you have is gene expression data from single cells, you need a way to identify and correct for the underlying factors that differentiate individual cells, so you can reveal the underlying biology," explains Oliver Stegle, Research Group Leader at EMBL-EBI.

Similarly, if you do not understand the difference between mutagenesis experiments and what has repeatedly been shown about nutrient-dependent RNA-mediated events that differentiate all cell types of all individuals in all tissues of all organs of all organisms of all species, you can never be more than an anonymous fool, like Andrew Jones (aka anonymous_9001) who based his review of my published work on his mutagenesis experiments. http://www.scribd...s#scribd

Jan 20, 2015
"A method for calculating probabilities of fitness consequences for point mutations across the human genome"

All that is left is ask is: "A method for calculating probabilities of fitness consequences for repair across the human genome"

Fairly obvious. The consequences of fitness are directly proportional to the daily number of DNA repairs. The repair has to be successful, not perfect. And this is the case.
Up to a million times daily per each and every cell in your body.
An occurrence that far outstrips the rate of any likely as well as unlikely mutation

This is part of normal brain activity:
http://medicalxpr...ain.html

Why stop there?
This process is a process of all living cells.
Why stop there?
The process is a process of all viruses.
Why stop there?
This process is the fundamental driver of evolution. Mutation just took a backseat to repair.
The paradigm shift can wait. While I gather the daily evidence and data.

Jan 20, 2015
Everything you've posted so far here is about alteration of expression, not genetic sequence, Kohl. Learn the difference, because it still seems like you think they're the same thing.

JVK
Jan 20, 2015
DNA repair is nutrient dependent. It is a fundamental process of ecological variation that typically leads to population-wide ecological adaptations via the metabolism of nutrients to species-specific pheromones that control the physiology of reproduction in species from microbes to man.

All cell type differentiation is nutrient dependent. Amino acid substitutions in viruses and light-induced amino acid substitutions in plants and in animals link the biophysically constrained chemistry of protein folding from non-living organisms to all extant biodiversity via the requirements Darwin referred to as 'conditions of life.' Only the biologically uninformed would ever have continued to accept de Vries definition of "mutation" and link their assumptions about natural selection to their ridiculous theories of evolution.

Thermodynamic cycles of protein biosynthesis and degradation are perturbed by mutations, which is why they do not lead to increasing organismal complexity.

Jan 20, 2015
Biologically uniformed science idiots do not understand the difference between RNA-directed DNA methylation that leads to amino acid substitutions and the stability of DNA in organized genomes, and mutations that lead to pathology.

And you don't, either.
Signed,
Just another "science idiot"...

Jan 20, 2015
DNA methylation that leads to amino acid substitutions


You run into a few problems with trying to explain all amino acid substitutions through DNA base substitutions resulting from methylation:

Not all substitutions are possible through this mechanism. Methylation followed by deamination only happens with cytosine. Unmethylated C deaminates into U, which is corrected with base excision repair. Methylated C deaminates into T.

It's not deterministic. The result of this mispair could be either the repair of the C or the T. There's no way to tell which, because unlike a mispair with U, repair enzymes can't tell which truly belongs. Deamination is also a spontaneous process. It could happen immediately following methylation or it could never happen.

http://www.web-bo...h7F1.gif

Because of this, methylation and deamination lead to... you guessed it- mutations:

http://www.ncbi.n...20846930

JVK
Jan 20, 2015
Of course I do, you science idiot. We detailed RNA-mediated cell type differentiation in our 1996 Hormones and Behavior review section on molecular epigenetics. Others are catching up. Science idiots like you never will.

http://www.hawaii...ion.html
1996 "Yet another kind of epigenetic imprinting occurs in species as diverse as yeast, Drosophila, mice, and humans and is based upon small DNA-binding proteins called "chromo domain" proteins, e.g., polycomb. These proteins affect chromatin structure, often in telomeric regions, and thereby affect transcription and silencing of various genes..."

http://genomebiol...5/12/537
2014 Through a variety of mechanisms acting on RNA, such as splicing, localization, and degradation, post-transcriptional regulation by RBPs also modulates protein abundance.

1996 "Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA ..."

Jan 21, 2015
You run into a few problems with trying to explain all amino acid substitutions through DNA base substitutions resulting from methylation:

Not all substitutions are possible through this mechanism. Methylation followed by deamination only happens with cytosine. Unmethylated C deaminates into U, which is corrected with base excision repair. Methylated C deaminates into T.

It's not deterministic. The result of this mispair could be either the repair of the C or the T. There's no way to tell which, because unlike a mispair with U, repair enzymes can't tell which truly belongs. Deamination is also a spontaneous process. It could happen immediately following methylation or it could never happen.
Because of this, methylation and deamination lead to... you guessed it- mutations:

Way cool explanation, Anon.

Jan 21, 2015
"All that is left is ask is: "A method for calculating probabilities of fitness consequences for repair across the human genome"

Fairly obvious. The consequences of fitness are directly proportional to the daily number of DNA repairs. The repair has to be successful, not perfect. And this is the case.
Up to a million times daily per each and every cell in your body.
An occurrence that far outstrips the rate of any likely as well as unlikely mutation

Why stop there?
This process is a process of all living cells.
Why stop there?
The process is a process of all viruses.
Why stop there?
This process is the fundamental driver of evolution. Mutation just took a backseat to repair.
The paradigm shift can wait. While I gather the daily evidence and data.

Russel,
As an un-informed "science idiot" in the room, I like where you are going with this. Explain to
JVK about ubiquitin and 26s proteasome and autophagy.
I look forward to your input on this.

Jan 21, 2015
At first sight ubiquitin is a collection of molecules. So is a garbage can. Ubiquitin tags the garbage it collects. A macroscopic garbage does this too (a fancy one). The garbage is sorted to be recycled or burned. You can trash JVK's model in the macroscopic garbage can. Highly unlikely the sorting process will tag or sort correctly what is to be recycled and what is to be burned of the model.

Not so on the microscopic scale where the bin (ubiquitin) for waste is never at a loss of what to be recycled and what is to be burned (ATP).

How am I doing?

Anyway, Anon is right. My claim also excludes mutation as the foremost way to alter gene expression. I, too always enjoy Anon corrections.

Instead I use repair. In an environment that changes overnight, a fast track change in gene expression for fast track adaptation is needed. Repair does this nicely until a mutation occurs and prevails for a long -enough-change that occurred overnight in the environment.

Jan 21, 2015
Typological corrections:
A macroscopic garbage [can] does this too (a fancy one).

Correctional addition in brackets... [ ]
See above.

JVK
Jan 21, 2015
You can trash JVK's model in the macroscopic garbage can.


George Church just used it in the context of genomic stability facilitated by a synthetic amino acid substitution in E. coli. http://www.scienc...5619.htm

Repair does this nicely until a mutation occurs and prevails for a long -enough-change that occurred overnight in the environment.


And then what? You science idiot!


Jan 21, 2015
26s proteasome is the microscopic version of your garbage disposal.
The macroscopic version is reserved for bigger things like worthless models.

JVK
Jan 21, 2015
http://www.eureka...2015.php

The researchers link nutrient-uptake to changes in the microRNA/messenger RNA balance that clearly are linked to RNA-directed DNA methylation and RNA-mediated amino acid substitutions that differentiate cell types.

The links are analogous to those that link nutrient uptake from the metabolism of nutrients to species-specific pheromones that control reproduction in species from microbes to man via the biophysically constrained chemistry of RNA-mediated protein folding.

For example, nutrient-dependent RNA-mediated events link metabolic networks to genetic networks in the context of pharmacogenomic testing that also links a single amino acid substitution to differences in the behavior of adolescent and adult human males. Differences in the behavior of female mosquitoes have been linked via amino acid substitutions to species diversity by Leslie Vosshall's group and from all crustaceans to all insects by others.

JVK
Jan 21, 2015
http://www.ncbi.n...2902798/

In the last 21 years it has become clear that the cellular "multicatalytic proteinase", conserved from archaebacteria to eukaryotes107, has central roles in all aspects of cell physiology.


In 1996, we linked nutrient-dependent RNA-mediated events and chromatin remodeling to the pheromone controlled physiology of reproduction in species from microbes to man via the conserved molecular mechanisms of cell type differentiation.

26s proteasome is the microscopic version of your garbage disposal.


It seems obvious that if you cannot place this into the context of thermodynamic cycles of protein biosynthesis and degradation that link biophysically constrained protein folding via amino acid substitutions in the cell type of all individuals of all species, that you should not be trashing my model.

JVK
Jan 21, 2015
Even Carl Zimmer seems at least one step closer to making creationist claims like Dobzhansky (1973) http://phenomena....y-today/

Like serious scientists, Zimmer appears to have realized there is a link between amino acid substitutions and cell type differentiation.

Dobzhansky wrote: "I am a creationist and an evolutionist." He thought that evolution occurred over millions of years via mutations. But he also noted that "...the so-called alpha chains of hemoglobin have identical sequences of amino acids in man and the chimpanzee, but they differ in a single amino acid (out of 141) in the gorilla." http://www.jstor..../4444260

That suggests nutrient-dependent amino acid substitutions differentiate the cell types of species from microbes to man. Zimmer reports "With a few years' work, they've made creatures that are probably unlike anything that ever lived on Earth." What creatures did mutations make?

Jan 21, 2015
Andrew Jones (aka anonymous_9001) who based his review of my published work on his mutagenesis experiments
@jk
Actually, from what i read, he was basing the review on your fallacious claims as well as inability to comprehend the science you were trying to spout off about

Especially considering your confusion of epigenetics and failure to recognize the possibility of beneficial mutations like the one in Lenski & Extavour's work because you don't understand biology

In fact, that is supported by the fact that you've YET to be able to comprehend a study you've linked yet with regard to biology
What creatures did mutations make?
still haven't learned to read, eh?
not surprising, given that you admitted to failing out of college because you didn't like being told that you would have to learn the basics (which you still haven't)

Jan 21, 2015
Way cool explanation, Anon.


Thanks. And unlike Kohl, I'm able to explain myself with specific names, enzymes, pathways, etc. Kohl merely says "organisms make substitutions, but I'm not going to tell you how". His explanations lack molecular details and I don't see that changing any time soon. The only mechanisms he's mentioned are splicing, which only alters mRNA, and methylation, which I've explained the limitations of and, big surprise, Kohl doesn't care what its limitations are because in his fantasy, its powers are limitless and it can do anything he wants it to do. Facts be damned.

But he also noted that "...the so-called alpha chains of hemoglobin have identical sequences of amino acids in man and the chimpanzee, but they differ in a single amino acid (out of 141) in the gorilla."


I don't know where you're getting the idea that anything labeled a substitution is automatically a positive change. Substitution is merely the term for a base changing to another.

Jan 21, 2015
At first sight ubiquitin is a collection of molecules. So is a garbage can. Ubiquitin tags the garbage it collects. A macroscopic garbage does this too (a fancy one). The garbage is sorted to be recycled or burned. You can trash JVK's model in the macroscopic garbage can. Highly unlikely the sorting process will tag or sort correctly what is to be recycled and what is to be burned of the model.

Not so on the microscopic scale where the bin (ubiquitin) for waste is never at a loss of what to be recycled and what is to be burned (ATP).

How am I doing?

Instead I use repair. In an environment that changes overnight, a fast track change in gene expression for fast track adaptation is needed. Repair does this nicely until a mutation occurs and prevails for a long -enough-change that occurred overnight in the environment.

Doin' fabulous...:-)

Jan 21, 2015
Substitutions, being the result of mutations, can be positive or negative.

http://www.ncbi.n...11922107

Pathogenic substitutions:

http://www.ncbi.n...25449070
http://www.ncbi.n...22240481
http://www.ncbi.n...10193512

Even Carl Zimmer seems at least one step closer to making creationist claims like Dobzhansky


Why don't you ask Zimmer yourself? Are you afraid he, like everyone Stumpy and I have contacted, will deny your claims and contradict you?

Jan 21, 2015
I don't know where you're getting the idea that anything labeled a substitution is automatically a positive change
@Anon
you already answered that above, in a way...

YOU give DETAILED explanations and also know what you are talking about... jk gives
"organisms make substitutions, but I'm not going to tell you how". His explanations lack molecular details and I don't see that changing any time soon
you are educated and everything he will never be

he is a pseudoscience creationist crackpot selling perfume to stupid teens and those who are not scientifically literate (or able to google, apparently)

this is one reason he hates you and i so much, as well as most others that he vilifies, like Myers, Lenski, Extavour and the rest...
because we stuck it out to get that paper that says "we're educated" whereas he failed out of college and went on to alchemy and guesswork
(and riding coattails... and lying about experience like "decades in diagnostic medicine")

Jan 22, 2015
Why don't you ask Zimmer yourself? Are you afraid he, like everyone Stumpy and I have contacted, will deny your claims and contradict you?
@Anonymous9001
I have tracked down his e-mail and decided to ask him myself... i am hoping to get a reply soon OR that he will simply show up here and clarify his article to jk

I knew jk wouldn't actually contact the author...
especially given that if he DID refute what jk said, it would be another mark against him
as well as another person for jk to publicly vilify and denigrate like Dr. Extavour, Lenski and all the others

but the best answer will also come from the SOURCE rather than jk's "interpretations"
which are usually so far off that they are almost hilarious

Jan 22, 2015
decades in diagnostic medicine

Like a long-term patient?

JVK
Jan 22, 2015
http://www.plantp...abstract]http://www.plantp...abstract[/url]

"Light is an important environmental signal that is directly perceived by the plant through photoreceptors and is essential for driving photosynthesis. As such, light provides the reducing power for carbon fixation, nitrogen assimilation, amino acid biosynthesis, and other necessary metabolic pathways. Information about light quality, intensity, and duration is measured through numerous photoreceptors (Mancinelli, 1994; Smith, 1994). Phytochromes are the primary red-light photoreceptors."

http://www.plantp...abstract]http://www.plantp...abstract[/url] "The influence on the pathogenic properties of the bacteria is at its strongest in this 'quorum sensing' system. P. asymbiotica requires dialkylresorcinol and in this way coordinates the communication with the conspecifics..."

This links biosynthesis of the new signal molecule to microbial luminescence in squid / microbe symbiosis.

JVK
Jan 22, 2015
...unlike Kohl, I'm able to explain myself with specific names, enzymes, pathways


That's easy to do when you link your ridiculous mutagenesis experiments to cause and effect after first eliminating everything known to serious scientists about physics and the chemistry of protein folding that's linked from light-induced amino acid substitutions in plants and animals to cell type differentiation in the bioluminescent microbes of squid via nutrient-dependent pheromone-controlled physiology of reproduction in both the squid and its bioluminescent microbes.

Like a long-term patient?


40 years as a Medical laboratory scientist (ASCP). For several years before I retired, I spent my workdays identifying the microbes that sometimes killed people who thought that the microbes mutated and became resistant to antibiotics, but also killed people who were not science idiots -- because the idiots don't know how microbes ecologically adapt.

Jan 22, 2015
That's easy to do when you link your ridiculous mutagenesis experiments to cause and effect after first eliminating everything known to serious scientists about physics and the chemistry of protein folding that's linked from light-induced amino acid substitutions in plants and animals to cell type differentiation


Funny how you respond to me saying you're always vague with another vague copied and pasted diatribe.

Jan 22, 2015
That's easy to do when you link your ridiculous mutagenesis experiments to cause and effect


What is it that you don't understand about those experiments? They isolate replication errors as the sole source of variety. There's nothing deliberately making the changes to the templates.

See: http://www.ncbi.n...16935245

JVK
Jan 25, 2015
Only a fool would try to bridge what is currently known about biology and the physical sciences via mutagenesis experiments.

Cell type differentiation is nutrient-dependent and I have detailed how it occurs in the context of the pheromone-controlled physiology of reproduction. Food odors and social odors (pheromones) are the information required for all interactions among all species (symbiosis). The basis for increasing organismal complexity is biological energy from the sun, not cosmic rays and mutations.

A quantum theory for the irreplaceable role of docosahexaenoic acid in neural cell signalling throughout evolution http://www.ncbi.n...23206328

Jan 25, 2015
Anyone who believes so is a fool and completely blind.


According to the man who is adamant his god put fossils into rocks when interior decorating the planet 6,000 yrs ago.

Jan 28, 2015
JVK's entire life long misguided endeavor can be summed up in one word:
Isomerism.

http://www.compou...omerism/

An excerpt:

"A prime, and well cited example of enantiomers with differing properties is that of the compound 'carvone'. In its (R) form, it is found in mint leaves, and is the principle contributor to the aroma. However, in its S form, it is found in caraway seeds, and has a very different smell."

The repair that all DNA undergoes continually since the dawn of DNA on earth is always, without exception, carried out with DNA isoforms. Mutation only occurs when repair (always done with DNA isoforms) is insuffienct, incomplete, or completely absent.

That is why the fundamental driver of evolution is repair.
That is why the fundamental driver of biodiversity is repair.
That is why the fundamental driver of cell differentiation is repair.
Repair synonymous with Isomerism.


Jan 28, 2015
Isomerism has many, many forms.
To demonstrate the potentiality of just one type of isomerism
the following excerpt is offered:

STRUCTURAL ISOMERISM

Isomers can be split into two broad groups – structural (or constitutional) isomers, and stereoisomers. We'll consider structural isomers first, which can be split again into three main subgroups: chain isomers, position isomers, and functional group isomers. Structural isomerism can quickly get quite out of hand in terms of the number of possible isomers; butane (four carbons) has two possible isomers, decane (ten carbons) has seventy-five, and a simple hydrocarbon containing 40 carbon atoms has an estimated 62,000,000,000 structural isomers.

http://www.compou...omerism/

Brace yourselves for the countless versions of JKVs (plus original) in the world.
And their antics.

JVK
Jan 29, 2015
Thanks. You fail to mention how repair occurs at the quantum level. For example, in my model "...methylation of the carbon-5 position of cytosine, which results in differences in 5hmCs, may be the most commonly studied type of nutrient-dependent pheromone-controlled structural and functional eukaryotic modification that results from organizing base pair changes."

You've linked to the math. Obviously, the organizing of the base pairs cannot be placed into the context of mutations. How does repair occur?

What do you refer to as my antics? To me, you sound like a science idiot who has never tried to link physics and chemistry from the sun's biological energy to communication required for life. See for example: Life is physics and chemistry and communication http://dx.doi.org...as.12570

If you are not just another science idiot, tell us how isomers become amino acid substitutions that differentiate all cell types in all individuals of all species.

Jan 29, 2015
Thanks. You fail to mention how repair occurs at the quantum level. - JVK


Conjecture is a wild goose chase for those willing to indulge. For the willing:
The fundamental nature of damage is to label damage as a random event.

"Superdeterminists do not recognize the existence of genuine chances or possibilities anywhere in the cosmos."
http://en.wikiped...erminism

That is my stance. I will convert to a quantum nature of repair when the existence of loopholes can not be upheld from logic or math.
Why?
All loopholes plugged is a signature for a path leading to the quantum nature of repair.
Until then, I'll pass. .


Jan 29, 2015
The postulate is; A life form without mutation will evolve too.
You assert nutrients and odors are sufficient for this.

You've linked to the math. Obviously, the organizing of the base pairs cannot be placed into the context of mutations. - JVK


Rhetorically how many different base pairs are there?
What physics disallow more than the base pairs we observe under the conditions we believe exist here on earth?


Jan 29, 2015
How does repair occur? - JVK


This is current research. Current research can assert there is no perfect repair.
Current research can assert errors. The consequences of errors is current research.

The consequences of repair leads to bold conclusions such as
"Scientists discover that DNA damage occurs as part of normal brain activity"

http://medicalxpr...ain.html

Neuroscience regards damage as bad.
You dismiss damage entirely.


JVK
Jan 29, 2015
You dismiss damage entirely.


"...methylation of the carbon-5 position of cytosine, which results in differences in 5hmCs, may be the most commonly studied type of nutrient-dependent pheromone-controlled structural and functional eukaryotic modification that results from organizing base pair changes."

It links DNA damage and DNA repair to the same conserved molecular mechanisms of cell type differentiation in all cells of all individuals of all species. Your claim that I dismiss damage entirely is one of the specious claims that science use to attack when they cannot defend their ridiculous theories.

All loopholes plugged is a signature for a path leading to the quantum nature of repair.
Until then, I'll pass. .


Your terminology is interesting since feedback loops are linked to the chromatin loops and genome stability via amino acid substitutions that plug the loopholes that lead to mutations and perturbed protein folding.

Jan 29, 2015
This is still relevant:

You run into a few problems with trying to explain all amino acid substitutions through DNA base substitutions resulting from methylation:

Not all substitutions are possible through this mechanism. Methylation followed by deamination only happens with cytosine. Unmethylated C deaminates into U, which is corrected with base excision repair. Methylated C deaminates into T.

It's not deterministic. The result of this mispair could be either the repair of the C or the T. There's no way to tell which, because unlike a mispair with U, repair enzymes can't tell which truly belongs. Deamination is also a spontaneous process. It could happen immediately following methylation or it could never happen.

http://www.web-bo...h7F1.gif

Because of this, methylation and deamination lead to... you guessed it- mutations:

http://www.ncbi.n...20846930

Jan 30, 2015
Great links. Much obliged.

JVK
Jan 30, 2015
(1996) "Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation in at least two species, Drosophila melanogaster and Caenorhabditis elegans..."
http://www.hawaii...ion.html

(2012) Alternative RNA Splicing in Evolution http://jonlieffmd...volution

"...alternative splicing may be the critical source of evolutionary changes differentiating primates and humans from other creatures such as worms and flies with a similar number of genes."

The anonymous fool (aka Andrew Jones) knows nothing about cell type differentiation. I co-authored the 1996 Hormones and Behavior review that set the stage for all other works that followed, including any that led to Jon Lieff's 2012 claim.

Jan 30, 2015
Is Adermatoglyphia a positive or negative nonsynonymous substitution?
Fixed? What selection is in play?


Jan 30, 2015
Also a great link. Also obliged.

Jan 30, 2015
http://jonlieffmd...bilities

"Since no one has been able to explain what a subjective experience is, and how it relates to the brain, all theories about the nature of the mind are speculative."

The answer here will help Lieff move on.

A subjective experience is the normal brain activity that causes DNA damage.
Since the retrieval of this damage is always synonymous with the retrieval of the repair to the damage caused, the experience will always be subjective.

No two repairs are alike. Repairs can be labeled 'successful' when more than one substitution result in a substitution indistinguishable from the an original sequence.

Unfortunately this does not guarantee the expression from the sequence remains the time.
Fortunately this guarantees our subjective sense for the passage of time.

Of course Lieff will refute this because his postulate is:
"Nothing is simply"
Too bad.

JVK
Jan 30, 2015
http://elifescien...fe.05290

Can anyone turn the Gly380Arg substitution into a beneficial mutation? If so, I may not use it as an example of how biophysically constrained nutrient-dependent amino acid substitutions are typically linked from RNA-mediated events to the chemistry of protein folding and cell type differentiation in all vertebrates (from coelacanths to primates) via the conserved molecular mechanisms of pheromone-controlled fixation of the amino acid substitutions.

I think it's a good example of biologically based cause and effect in 500 different stickleback ecotypes and all other vertebrates, but claims of beneficial mutations must also be examined for comparison. If the Gly380Arg substitution can't be turned into a beneficial mutation, please provide an example of a different mutation that links cell types in all vertebrates to their evolution.

Feb 02, 2015
Hmm.
Claudia Waskow has the perfect volunteer candidate for a beneficial mutation.
http://medicalxpr...tml#nRlv

Of course this falls short of a mutation that links cell types in all vertebrates to their evolution.

Of mice and men......an excerpt:

"In the new model human blood stem cells can expand and differentiate into all cell types of the blood without any additional treatment.".

We all know nothing impresses you.

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