Molecular movement in living matter

Evolution, Natural Selection, Medicine, Psychology & Neuroscience.

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Re: Molecular movement in living matter

#201  Postby GenesForLife » Jun 06, 2012 10:36 pm

Well I'd say that is fairly trivial. Observations are showing that these chromosomes are not static substances but move and interact in precise ways and there are some really interesting questions being asked as shown here


Actually, local interactions aren't necessarily incompatible with the equilibrium-based spontaneous organisation model that has been proposed. For instance, such interactions could quite simply be altering equilbrium, and consequently the organisation that forms. There is already evidence that nucleosome modifications can affect conformation, either directly (histone acetylation) or by recruitment of proteins that distort original structures (histone methylation) for instance and I wouldn't be surprised if the effects of chromosome kissing contribute in some way to altered conformation of chromatin locally, and consequently, which territories they seem to occupy.
Last edited by GenesForLife on Jun 07, 2012 7:48 pm, edited 1 time in total.
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Re: Molecular movement in living matter

#202  Postby Rumraket » Jun 07, 2012 5:36 pm

In any case, all this waffling around about stuff we haven't yet fully described isn't even remotely (in fact, not at all) bridging the gap from the knowledge that "This system exists and large parts of it behaves like this, and there's some stuff here we don't yet know" to "And it was teleologically preplanned and guided to be what it is today, from the top down, starting billions of years ago".

As much as I enjoy having someone competent and willing to explain (GFL :thumbup: ) endlessly bring up interesting facts, this discussion is going nowhere because CharlieM is just mindlessly regurgitating knowledge-gaps with the a-priory faith that this some day, in some hitherto completely obscure way, is going to show he was right about his weird guidance and pre-planning towards conscious and loving, "archetypical" perfect, infinitely complex, multicellular beings, all along.

Seriously... what the fuck? :scratch:
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Re: Molecular movement in living matter

#203  Postby GenesForLife » Jun 07, 2012 7:54 pm

It's basically like he's pointed to loads of interesting epigenetic phenomena, which are interesting enough as they are, but I don't really see where he's going with this. It appears to be a statement of "Genes alone cannot explain development/physiology, ergo there is something else co-ordinating everything, including genes". At the moment he's trying to pin chromatin biology as the source of everything else, including gene expression.
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Re: Molecular movement in living matter

#204  Postby CharlieM » Jun 13, 2012 3:26 pm

GenesForLife wrote:It's basically like he's pointed to loads of interesting epigenetic phenomena, which are interesting enough as they are, but I don't really see where he's going with this. It appears to be a statement of "Genes alone cannot explain development/physiology, ergo there is something else co-ordinating everything, including genes". At the moment he's trying to pin chromatin biology as the source of everything else, including gene expression.


Well I'm not alone in thinking that genes alone can't explain development:

http://sse.royalsociety.org/2012/exhibits/epigenetics-exposed/
Genes provide the basic instructions for what we look like, our personalities, and what diseases we may develop. However, genes alone cannot explain how our body and our organs develop, nor all aspects of inheritance or why diseases arise.


http://www.dnafiles.org/programs/beyond-human
Clearly, genes alone can't explain the complexity, diversity, and development of life on Earth, so what do they mean?


http://www.bric.ku.dk/newslist/news/research_in_cellular_memory/
"After the mapping of the human genome, it became clear that genes alone cannot explain the complexity of life. Genes need to be turned on or off in a specific order, to enable development of the 200 cell types in our body and to sustain their normal function throughout life. We have developed a new technology, which we can use to gain insight into how cellular memory is maintained when cells divide," says Anja Groth.


*
http://www.sciencedaily.com/releases/2009/04/090416144639.htm
Genes alone cannot explain the vast differences in complexity among worms, mice, monkeys and humans, all of which have roughly the same amount of genetic material. Scientists have found that these differences arise in part from the dynamic regulation of gene expression rather than the genes themselves. Epigenetics, a relatively young and very hot field in biology, is the study of nongenetic factors that manage this regulation...

The discovery of a new nucleotide may make biologists rethink their approaches to investigating DNA methylation. Ironically, the latest addition to the DNA vocabulary was found by chance during investigations of the level of 5-methylcytosine in the very large nuclei of Purkinje cells, says Skirmantas Kriaucionis, a postdoctoral associate in the Heintz lab, who did the research. "We didn't go looking for this modification," he says. "We just found it."


http://www.nature.com/news/fruitfly-genome-mapped-in-three-dimensions-1.9859
Chromosomes and their genes are arranged in a specific way throughout the nucleus, and because the nucleotide sequence of a genome alone cannot explain the functions of its genes, researchers have started investigating how the spatial organization of genes might affect how they work.

“Conceptually, we’re entering a new era,” says study author Giacomo Cavalli, of the Institute of Human Genetics in Montpellier, France. “Forty years ago we looked at single genes, now we know we need to look at them in context — that’s the 3D folding of chromosomes.


http://www.childup.com/blog/the-ultimate-brain-quest
Neuroscientists posit that all of our hopes, desires, beliefs and experiences are encoded in the brain as patterns of neural firings. Just how this happens is not precisely understood, as the author attests, but we have made great strides in understanding how neurons communicate with one another. Progress has also been made in mapping which brain systems control which kinds of operations (my own field of research): One system is responsible for lifting your foot, another senses the pain when you stub your toe; one system helps you to solve arithmetic problems, another enjoys "La Bohème." A new approach to studying brains and individual differences involves making maps of how neurons connect to one another. Following the term genome, these are called connectomes.

"Why study connectomes if genomics is already so powerful?" Mr. Seung asks. "The answer is simple: Genes alone cannot explain how your brain got to be the way it is. As you lay nestled in your mother's womb, you already possessed your genome but not yet the memory of your first kiss."



So what else other than the genome can influence and control development. See here:

Please cite this article in press as: Levin, M., Morphogenetic fields in embryogenesis, regeneration, and cancer: Non-local control of complex patterning. BioSystems (2012), http://dx.doi.org/10.1016/j.biosystems.2012.04.005

The geometric shape of the substrate upon which cells reside has crucial implications for their future behavior (Chen et al., 1997, 1998; Huang and Ingber, 2000); this geometry is an ideal example of a signal that cannot be described by genetic or proteomic profiling alone. Additional physical properties that can serve similar functions include mechanical properties of tissues (Beloussov, 2008; Beloussov and Grabovsky, 2007; Beloussov and Lakirev, 1991; Beloussov et al., 2000, 1997; Brodland et al., 1994; Discher et al., 2005; Savic et al., 1986), ultraweak photon emission (Beloussov, 2001; Popp, 2003), and bioelectrical gradients (Levin, 2007b, 2009, 2011a, 2012).


In experiments with planaria they developed 2-headed forms from tissue taken from normal animals. They had this to say:

Thus, a line of such 2-headed animals could be maintained, which would be identical in DNA sequence to the normal 1-headed worms and yet have radically different behavior and body-plan architecture. The evolutionary implications of this are apparent, and demonstrate that the biophysical, epigenetic aspects of patterning may play an important role in evolution, as selection operates on animal morphologies. Thus, it is likely that a full understanding of the morphogenetic field and its informational content will need to involve cracking the bioelectric code (the mapping between spatiotemporal ionic profile patterns and tissue morphology outcomes).


They give an example of a development which takes recognises and adjusts for deviations from the normal pattern.

Importantly however, large-scale morphostasis does not simply depend on recapitulating fixed developmental programs (Voskoboynik et al., 2007). For example, the tadpole face is quite different from that of a frog; during metamorphosis, a series of deformations must be executed and various organs and tissues displaced towards their appropriate locations. Remarkably, when developmental defects were induced in the tadpole (by manipulating the embryonic voltage gradients that guide craniofacial patterning), subsequent development was able to adjust accordingly (Vandenberg et al., 2012). Most organs were still placed into the right final positions, using movements quite unlike the normal events of metamorphosis, showing that what is encoded is not a hardwired set of tissue movements but rather a flexible, dynamic program that is able to recognize deviations, perform appropriate actions to minimize those deviations, and stop rearranging at the right time. Even the highly-mosaic C. elegans embryo can re-route cells through far-ranging movements (Schnabel et al., 2006) to counteract experimental perturbations.


The passage below suggests that researchers are reluctant to follow any evidence that threatens the current understanding because they fear where it will lead. This is the attitude that is holding science back.

Target morphology models are eschewed in biology today, mainly because of a fear of teleology (Ruse, 1989; Teufel, 2011) harkening back to the early days of preformationism, and because the field has made such progress by focusing on the difficult problem of cellular-level controls. However, there are data that suggest that prepattern models should be considered...

One set of results that suggests a target morphology model is the trophic memory in deer antlers discussed above. If there is a target morphology for the rack shape encoded directly in some way, it is easy to see how changes of that shape can be long-lived. An injury to a specific place on one tine may induce a physical change in the map structure at the corresponding location (e.g., a change in a neural network storing the morphology), causing the extra tine to be reca-pitulated in subsequent years as the antlers grow and cells “consult” (are controlled by) the map. In contrast, an emergent model views the antler rack shape as the result of purely local decisions made by cells during their growth period. The question this system would have to solve is: how to modify the rules of cell growth to result in exactly the same rack shape plus one extra tine at the specified loca-tion? This is an excellent example of an inverse problem (Fig. 3C), and is in general computationally intractable—there is no way for the system to know how the cell behavior rule set is to be modified to result in the desired pattern. This seems to be a situation in which a map model would be preferable, and indeed a priori, the emergent model wrongly predicts that such a phenomenon should not exist.


Below we see an example of someone looking at the evidence (humans are more capable than chimpanzees of breaking down starch) and telling us how this error must have happened. They find it impossible to imagine that human eating habits were responsible for this ability. They seem to believe we took advantage of an accidental mutation.

From New Scientist 9 June 2012, p39:

A digestive enzyme called salivary amylase plays a key role in breaking down starch into simple sugars so it can be absorbed in the gut. Humans have much higher levels of amylase in their saliva than chimpanzees, and recently it was discovered how this came about.

While chimps have only two copies of the salivary amylase gene (one on each of the relevant pair), humans have an average of six, with some people having as many as 15 (Nature Genetics, Vol 39, p1256). DNA copying errors during the production of sperm and eggs must have led to the gene being repeatedly duplicated.

To find out when the duplications happened, the gene was sequenced in people from several countries, as well as in chimps and bonobos, "We were so hoping to find a signature of selection about 2 million years ago, " says Nathaniel Dominy, a biological anthropologist now at Dartmouth College in Hanover, New Hampshire, who led the work. That is around the time our brains underwent significant growth , and one theory is that it was fuelled by a switch to a starchier diet.

But the team found the gene duplications had happened more recently-some time between 100 000 years ago and the present day. The biggest change i that period was the dawn of agriculture, so Dominy thinks the duplications happened when we started farming cereals. "Agriculture was a signal event in human evolution ," he says. "We think amylase contributed to it."

It was the advent of agriculture that allowed us to live in large settlements, which led to innovation, the cultural explosion and, ultimately, modern life. If we consider all the mutations that led to these pivotal point in our evolution, human origins begin to look like a trail of unfeasible coincidences. But that is only because we do not see the harmful mutatios that were weeded out, points out John Hawks at the University of Wisconsin-Madison. "What we're left with is the ones that were advantageous." It is only from today's viewpoint that the mutations that give us our current physical form appear to be the "right" ones to have. "It's hindsight," says Hawks. "When we look back at the whole process, it looks like a stunning series of accidents."



The problem with his scenario above is that amylase production seems to match dietary habits and there is no reason to infer that duplication of the amylase gene is a harmful mutation. So the accident occurs in just those groups that can make use of it.

From this article:
Although it is possible that lower AMY1 gene copy numbers have been favored by selection in low-starch populations, such an interpretation is less plausible for the simple reason that excessive amylase production is unlikely to have a significant negative effect on fitness.


So, overall, although some are still stuck in the past we do see evidence that the gene centred view of life is beginning to be superceded, and not before time.
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Re: Molecular movement in living matter

#205  Postby CharlieM » Jun 13, 2012 3:33 pm

GenesForLife wrote:As for your top-down claims, top down regulation from where? by what?


Here are instances of a top-down explanation positing morphogenetic fields:


Please cite this article in press as: Levin, M., Morphogenetic fields in embryogenesis, regeneration, and cancer: Non-local control of complex patterning. BioSystems (2012), http://dx.doi.org/10.1016/j.biosystems.2012.04.005

“Cancer is no more a disease of cells than a traffic jam is a disease of cars. A lifetime study of the internal combustion engine would not help anyone to understand our traffic problems” (Smithers, 1962). The hypothesis that cancer is fundamentally a phenomenon at the level of multicellular organization makes a number of predictions confirmed by experimental data. Cells in dispersed monolayer culture are several orders of magnitude more sensitive to chemical carcinogenesis than are organized tissues within an intact organism (Parodi and Brambilla, 1977), and placing normal primary mammalian cells in culture results in the appearance of cells with malignant potential Newt regeneration blastemas exposed to carcinogenic chemicals or ultraviolet radiation produce ectopic limbs or lenses, not tumors (Breedis, 1952; Butler and Blum, 1955; Eguchi and Watanabe, 1973), demonstrating the ability of actively patterning tissues to suppress tumorigenesis and highlighting the possibility that cancer induction and large-scale patterning disorganization (ectopic organs) are different points on a single axis.
[and]

... in the pronephric duct of polyploidy salamanders, cell size can increase without increase in diameter of the duct, so that the number of cells in cross-section can go down from the normal 8 to even just one, which will still fold over to create the appropriate lumen (Fankhauser, 1945). Pattern is primary and multi-cellularity isn’t crucial...
The current paradigm focuses on cell-level activity (prolifera-tion, differentiation, migration), but might tissue- or organ-level systems properties be the right basal concepts with which to explain adaptive shape repair, anatomical polarity, and size con-trol? At the level of pathways, stem cells and cancer cells share many similarities (Dreesen and Brivanlou, 2007; Reya et al., 2001; White and Zon, 2008); patterning influence is needed to push them towards a coherent, developmental program vs. cancerous prolif-eration. Similarly, anatomical context is crucial to the fate of stem cells and needs to be taken into account when designing molecu-lar strategies for driving stem cells towards specific behaviors. For example, transduction with a cocktail of transcription factors suffi-cient to induce an eye from a group of multipotent progenitor cells, but it only does so when implanted into a host, not in vitro (Viczian et al., 2009). The morphogenetic field concept is most compatible with a top-down view, focused on information flow {(what do cells need to know in order to build or repair a structure? in what form is encoded the final morphology of any given organ or bodyplan?), as distinct from the more popular bottom-up molecularly-focused approach (what does protein X bind to? which genes does transcription factor Y activate or repress?).
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Re: Molecular movement in living matter

#206  Postby DavidMcC » Jun 13, 2012 4:40 pm

CharlieM wrote:“Cancer is no more a disease of cells than a traffic jam is a disease of cars

BS! Cancer is essentially a failure of the cell to respond to apoptosis signals, like FADD. Phosphorylation of FADD causes it to fail to precipitate cell death, leading to uncontrolled cell division and growth, ie, cancer.
http://www.nature.com/bjc/journal/v94/n4/full/6602955a.html
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Re: Molecular movement in living matter

#207  Postby CharlieM » Jun 14, 2012 12:19 am

DavidMcC wrote:
CharlieM wrote:“Cancer is no more a disease of cells than a traffic jam is a disease of cars

BS! Cancer is essentially a failure of the cell to respond to apoptosis signals, like FADD. Phosphorylation of FADD causes it to fail to precipitate cell death, leading to uncontrolled cell division and growth, ie, cancer.
http://www.nature.com/bjc/journal/v94/n4/full/6602955a.html



Well some experts, even unabashed geneticists, who study these things day in and day out, think we have to look beyond the cell to understand cancer:

http://www.nytimes.com/2009/12/29/healt ... wanted=all

Mina Bissell will never forget the reception she got from a prominent scientist visiting Lawrence Berkeley National Laboratory, where she worked. She gave him a paper she had just published on the genesis of cancer.
“He took the paper and held it over the wastebasket and said, ‘What do you want me to do with it?’ Then he dropped it in.”

That was 20 years ago, and ever since, Dr. Bissell and a few others have struggled for acceptance of what seemed a radical idea: Gene mutations are part of the process of cancer, but mutations alone are not enough. Cancer involves an interaction between rogue cells and surrounding tissue...

The basic idea — still in the experimental stages — is that cancer cells cannot turn into a lethal tumor without the cooperation of other cells nearby. That may be why autopsies repeatedly find that most people who die of causes other than cancer have at least some tiny tumors in their bodies that had gone unnoticed. According to current thinking, the tumors were kept in check, causing no harm...

The researchers are cautious. They, more than anyone else, know the blind alleys of cancer research over the past few decades. And no one is suggesting that controlling a tumor’s environment will, by itself, cure cancer.

And they are not discounting cancer-causing genes. But even some who have made their careers studying cancer genes say a tumor’s environment can no longer be ignored.

“I am an unabashed cancer geneticist,” said Dr. Bert Vogelstein, director of the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins. “The genetic alterations in the cancer cells are the proximate cause of the malignancy.”

But, Dr. Vogelstein said, “one cannot fully understand that disease unless one understands” the tumor’s environment.
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Re: Molecular movement in living matter

#208  Postby GenesForLife » Jun 14, 2012 8:14 am

DavidMcC wrote:
CharlieM wrote:“Cancer is no more a disease of cells than a traffic jam is a disease of cars

BS! Cancer is essentially a failure of the cell to respond to apoptosis signals, like FADD. Phosphorylation of FADD causes it to fail to precipitate cell death, leading to uncontrolled cell division and growth, ie, cancer.
http://www.nature.com/bjc/journal/v94/n4/full/6602955a.html


Um, partly but not quite. That is just one of the hallmarks of cancer, and cells need to exhibit all of them to qualify as cancerous. (See Hanahan and Weinberg, The Hallmarks of Cancer).

http://www.cell.com/abstract/S0092-8674%2811%2900127-9
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Re: Molecular movement in living matter

#209  Postby DavidMcC » Jun 14, 2012 8:24 am

]The first thing she noticed was that when D.C.I.S. broke free of a milk duct, the duct’s outer layer had broken down. It could be that the duct falls apart because the cancer is bursting out. Or it could be that the cancer is escaping the duct because the outer layer disintegrated — which is what her research showed. As long as the milk duct is intact, D.C.I.S. cells cannot escape.

Charlie, what they describe here is one of the body's anti-cancer mechanisms, which limit a malignant tumour's ability to grow and spread. This one seems to be specific to breast cancer. The cell causing the problem is still diseased, even if that disease can sometimes be kept in check.
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Re: Molecular movement in living matter

#210  Postby DavidMcC » Jun 14, 2012 8:27 am

That may be why autopsies repeatedly find that most people who die of causes other than cancer have at least some tiny tumors in their bodies that had gone unnoticed. According to current thinking, the tumors were kept in check, causing no harm...

These are known as "benign tumours". Skin moles are also benign tumours.
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Re: Molecular movement in living matter

#211  Postby GenesForLife » Jun 14, 2012 8:42 am

The problem with his scenario above is that amylase production seems to match dietary habits and there is no reason to infer that duplication of the amylase gene is a harmful mutation. So the accident occurs in just those groups that can make use of it.


Here's the source of your confusion. The mutation doesn't occur in groups that make use of it, it is fixed in populations that do. I'll let you figure out what the difference is between a mutation occurring for a certain reason and a random mutation getting fixed in a population for a particular reason.

You essentially look at what mutations were fixed and go "Ooh, the mutation occurred to give us an advantage" but as your very own source points out, you would be well advised to read and assimilate this.

. If we consider all the mutations that led to these pivotal point in our evolution, human origins begin to look like a trail of unfeasible coincidences. But that is only because we do not see the harmful mutatios that were weeded out, points out John Hawks at the University of Wisconsin-Madison. "What we're left with is the ones that were advantageous." It is only from today's viewpoint that the mutations that give us our current physical form appear to be the "right" ones to have. "


I suggest you find some of Susu.exp's posts on the distribution of mutations and you will know exactly where your idea of organisms developing mutations to meet future needs goes awry. I will search for some of them later and will post them here.

You have given the example of the stromal environment in cancer as an example of top-down regulation. I disagree - a process that involves cross-talk between cells and feedback from said cross-talk is not top-down. It is bottom up with feedback.

Also, the role of stromal cells has been known for a long time, as have the disadvantages of monolayer studies in elucidating the process of carcinogenesis, since gene expression patterns are known to vary with spatial architecture, being regulated by the cell modifying transcriptional programs by sensing for external cues.

And that tumour stroma influences cancer cells has been known for a long time as well.
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Re: Molecular movement in living matter

#212  Postby DavidMcC » Jun 15, 2012 10:59 am

GenesForLife wrote:Um, partly but not quite. That is just one of the hallmarks of cancer, and cells need to exhibit all of them to qualify as cancerous. (See Hanahan and Weinberg, The Hallmarks of Cancer).


I thought you might nit-pick, but I wasn't trying to describe everything, and that in turn is because it isn't necessary to the point at issue, that cancer is a disease of cellular biology, in that the cancerous cell is unable to die, an abnormal state, that makes it a cause of disease for the organism that ultimately sustains that cell.
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Re: Molecular movement in living matter

#213  Postby DavidMcC » Jun 15, 2012 11:14 am

... To use CharlieM's traffic jam analogy, a cancerous cell is like a car that's lost its brakes, in a busy road network - bound to cause trouble eventually.
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Re: Molecular movement in living matter

#214  Postby CharlieM » Jun 19, 2012 12:30 pm

GenesForLife wrote:
The problem with his scenario above is that amylase production seems to match dietary habits and there is no reason to infer that duplication of the amylase gene is a harmful mutation. So the accident occurs in just those groups that can make use of it.


Here's the source of your confusion. The mutation doesn't occur in groups that make use of it, it is fixed in populations that do. I'll let you figure out what the difference is between a mutation occurring for a certain reason and a random mutation getting fixed in a population for a particular reason.

You essentially look at what mutations were fixed and go "Ooh, the mutation occurred to give us an advantage" but as your very own source points out, you would be well advised to read and assimilate this.

. If we consider all the mutations that led to these pivotal point in our evolution, human origins begin to look like a trail of unfeasible coincidences. But that is only because we do not see the harmful mutatios that were weeded out, points out John Hawks at the University of Wisconsin-Madison. "What we're left with is the ones that were advantageous." It is only from today's viewpoint that the mutations that give us our current physical form appear to be the "right" ones to have. "


You are assuming that these duplications are accidental mutations that became fixed in various human populations at an unspecified time in the past 100 000 years. But as P.Z.Myers says:
(The amylase gene) seems to be in a hotspot for duplication, and different people have different numbers of copies of the gene. If you just had one copy of the gene per chromosome, your cells would each have a grand total of two copies…but instead, we more typically have 5 to 7, with some people having only 2, and others having 15 or more.


So it is difficult to figure out in what way they are fixed. We are talking here of salivary amylase gene copy number variation. Copy number variation has been shown to occur between monozygotic twins who presumably started out with identical genomes. In other words if they can't be shown to be fixed even in an individual how can they be shown to be fixed in an unobserved population?

Ellison Medical Foundation
We have recently shown that monozygotic twins frequently differ in their genes by changes in so called copy number variation (CNV), which represent one type of genetic differences that can be frequently seen between any two unrelated people.


So in what way are they fixed?

GenesForLife wrote:
I suggest you find some of Susu.exp's posts on the distribution of mutations and you will know exactly where your idea of organisms developing mutations to meet future needs goes awry. I will search for some of them later and will post them here.


I am not talking about an organism meeting future needs. I'm talking about organisms responding to a high intake of starch.

I'd be interested to know if any research has been carried out in order to determine if amylase copy numbers vary within one individual. For example between DNA extracted from an individual's saliva and say stem cells from the same individual.

I did find this but they don't mention amylase and I haven't had time to read through it yet.
The exploration of copy-number variation (CNV), notably of somatic cells, is an understudied aspect of genome biology. Any differences in the genetic makeup between twins derived from the same zygote represent an irrefutable example of somatic mosaicism. We studied 19 pairs of monozygotic twins with either concordant or discordant phenotype by using two platforms for genome-wide CNV analyses and showed that CNVs exist within pairs in both groups.
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Re: Molecular movement in living matter

#215  Postby CharlieM » Jun 19, 2012 12:39 pm

DavidMcC wrote:... To use CharlieM's traffic jam analogy, a cancerous cell is like a car that's lost its brakes, in a busy road network - bound to cause trouble eventually.


Its not my analogy, I was just quoting an article which in turn quoted D.W. Smithers who wrote the statement.
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Re: Molecular movement in living matter

#216  Postby GenesForLife » Jun 19, 2012 6:50 pm


So it is difficult to figure out in what way they are fixed. We are talking here of salivary amylase gene copy number variation. Copy number variation has been shown to occur between monozygotic twins who presumably started out with identical genomes. In other words if they can't be shown to be fixed even in an individual how can they be shown to be fixed in an unobserved population?


[1] Somatic mosaicism is irrelevant to evolution. Germline mutations are. The fact that you get massive variations in regions of the genome in somatic cells does not actually impact how the mutation is fixed or inherited. If said variations are due to hotspots of duplication, those hotspots themselves will be subject to selection. To sum up, evolvability itself is potentially a selectable trait.

Also, since you mention unobserved populations, we use the general statistical tools of Confidence Intervals that facilitate extrapolations from observed populations.

[2] It is rather amusing to confuse the fixation of mutations/alleles with fixations of copy numbers themselves. See previous point for an explanation of why this is the case.

[3] New CNVs can occur in the presence of pre-existing ones just like new SNPs can form in the background of pre-existing ones, unless of course there is an initial loss of copy number to the point of eliminating the gene.
In the case of loci prone to massive copy number variations, that itself is selected for or prone to elimination. Just like SNPs, CNVs also have a distribution that ranges from being beneficial to being deleterious (generally tending towards being deleterious http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2577867/ ), you still don't get organisms developing CNVs by choice to meet particular needs to eventually meet their visions of some kind of archetype. While cellular stress does seem to increase the accumulation of CNV's, there is no arbitrary trend in favour of beneficial CNVs, for instance.

[4] I am not mistaking the duplication for a single change that happened so many years ago et cetera. CNVs and SNPs may have different mechanisms by which they come about (involvement of DSB repair mechanisms for CNVs as opposed to polymerase proofreading errors for SNPs) but the principle is still the same...in terms of fitness effects you get a spectrum subject to natural selection.
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Re: Molecular movement in living matter

#217  Postby DavidMcC » Jun 20, 2012 9:58 am

CharlieM wrote:
DavidMcC wrote:... To use CharlieM's traffic jam analogy, a cancerous cell is like a car that's lost its brakes, in a busy road network - bound to cause trouble eventually.


Its not my analogy, I was just quoting an article which in turn quoted D.W. Smithers who wrote the statement.

Whatever. The point is that you obviously supported fairly strongly.
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Re: Molecular movement in living matter

#218  Postby Rumraket » Jun 20, 2012 11:02 am

GenesForLife wrote:While cellular stress does seem to increase the accumulation of CNV's, there is no arbitrary trend in favour of beneficial CNVs, for instance.

This is the key phrase here I think. If one were to postulate that CNV's were somehow being intentionally guided into place, because the organism in question "needs" them in order to adapt to some environmental stress, you'd expect them to only or maybe just mostly show up in areas where they positively affect the fitness of the organism.
You could test this claim with an experiment along these lines: Have a population of sufficiently complex but fast-growing single-celled eucaryotes, like yeast, grow under stable conditions in some set medium for an extended period and record the areas of the genome where CNV's show up and how often/likely they are. Now change the growth-medium to one that has a high concentraton of some nutrient which, if the organism had more copies of a relevant enzyme-producing gene, would increase it's fitness, and record the frequency and locations of CNV's again.
If CNV's were being guided for the benefit of the organism, you'd expect an increased frequency of CNV's in the enzyme-coding loci. But if evolution, as it is normally understood by the scientific community, is true, then you'd expect a random distribution of CNV's irrespective of loci. Only the frequency should go up, if at all.
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Re: Molecular movement in living matter

#219  Postby GenesForLife » Jun 20, 2012 3:27 pm

Rumraket wrote:
GenesForLife wrote:While cellular stress does seem to increase the accumulation of CNV's, there is no arbitrary trend in favour of beneficial CNVs, for instance.

This is the key phrase here I think. If one were to postulate that CNV's were somehow being intentionally guided into place, because the organism in question "needs" them in order to adapt to some environmental stress, you'd expect them to only or maybe just mostly show up in areas where they positively affect the fitness of the organism.
You could test this claim with an experiment along these lines: Have a population of sufficiently complex but fast-growing single-celled eucaryotes, like yeast, grow under stable conditions in some set medium for an extended period and record the areas of the genome where CNV's show up and how often/likely they are. Now change the growth-medium to one that has a high concentraton of some nutrient which, if the organism had more copies of a relevant enzyme-producing gene, would increase it's fitness, and record the frequency and locations of CNV's again.
If CNV's were being guided for the benefit of the organism, you'd expect an increased frequency of CNV's in the enzyme-coding loci. But if evolution, as it is normally understood by the scientific community, is true, then you'd expect a random distribution of CNV's irrespective of loci. Only the frequency should go up, if at all.


Irrespective of fitness, actually. One of the possible mechanisms proposed for CNVs at hotspots is microhomology mediated break-induced replication, and you would then get CNVs at regions prone to this, but they won't all be beneficial. If an MMBIR prone region consistently leads to deleterious CNVs we should then expect to see selection against those sequences being in those regions.
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Re: Molecular movement in living matter

#220  Postby Rumraket » Jun 20, 2012 6:04 pm

GenesForLife wrote:
Rumraket wrote:
GenesForLife wrote:While cellular stress does seem to increase the accumulation of CNV's, there is no arbitrary trend in favour of beneficial CNVs, for instance.

This is the key phrase here I think. If one were to postulate that CNV's were somehow being intentionally guided into place, because the organism in question "needs" them in order to adapt to some environmental stress, you'd expect them to only or maybe just mostly show up in areas where they positively affect the fitness of the organism.
You could test this claim with an experiment along these lines: Have a population of sufficiently complex but fast-growing single-celled eucaryotes, like yeast, grow under stable conditions in some set medium for an extended period and record the areas of the genome where CNV's show up and how often/likely they are. Now change the growth-medium to one that has a high concentraton of some nutrient which, if the organism had more copies of a relevant enzyme-producing gene, would increase it's fitness, and record the frequency and locations of CNV's again.
If CNV's were being guided for the benefit of the organism, you'd expect an increased frequency of CNV's in the enzyme-coding loci. But if evolution, as it is normally understood by the scientific community, is true, then you'd expect a random distribution of CNV's irrespective of loci. Only the frequency should go up, if at all.


Irrespective of fitness, actually.

Wouldn't that be both? Maybe I could have expressed myself more clearly. Say CNV's are mostly restricted to hotspots in a few places in the genome, but only CNV's in one loci(that enzyme coding gene) has the potential for a direct benefit to the organism. Now, just because CNV's in that location are possibly beneficial it doesn't mean CNV's have a higher frequency of occurrence in that region, compared to their earlier recorded frequency in the same region. That's what I meant with irrespective of loci.

GenesForLife wrote:One of the possible mechanisms proposed for CNVs at hotspots is microhomology mediated break-induced replication, and you would then get CNVs at regions prone to this, but they won't all be beneficial. If an MMBIR prone region consistently leads to deleterious CNVs we should then expect to see selection against those sequences being in those regions.

Of course, but that would be selection against fixation, not frequency of occurrence.
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