What is the solid evidence for random (meaning not epigenetic) causes for successful gene mutation?

[lordcheesehorn]

Hello. I would like to know what solid evidence there is that successful genetic modifications are caused by random survivial-selected mutations and not through the epigenetic influence of the organism or the environment.

Many thanks for your time.

[CharonY]

Well, evidence is pretty much ubiquitous. But if you are thinking in terms of controlled lab experiment, one typical undergrad experiment is to take bacteria that are not able to grow under a given condition (e.g. auxotrophic mutants that require feeding with amino acids, or antibiotic sensitive strains) and expose them to a mutagen (not strictly necessary, but it increases mutation rate and accelerates the experiment).

 

Then plate them onto restrictive media (i.e. either lacking the necessary nutrient or with a low amount of antibiotics). Usually there are a few colonies growing indicating that they had mutations that allow them to grow on the respective media before they actually ever encountered that situation. The experiments by Lenski are somewhat similar only on a much longer scale and with larger phenotypic changes.

[lordcheesehorn]

Thanks... but either a) I don’t understand your answer or b) I didn’t phrase my question properly. I fear a)...

 

What proves that it is random mutations that select for survival rather than the influence of the context / environment / phenotype / organism or anything else? Seems to me that in the case of the experiment you mention there is no proof that, in the wild, such bacteria couldn’t mutate towards survival-friendlier states under the pressure of a changing situation? What proves that eyes evolved entirely through random mutations and not through some mechanism whereby the gene responds to the environment somehow?

[CharonY]

The bacteria are grown under non-selective conditions. I.e. the auxotrophy or sensitivity has no bearing on their survivability. As such the mutations would be neutral under the given circumstances, but turn beneficial under selective conditions. They the molecular mechanisms would have no way to peak into the future there cannot be any specific changes.

 

One should also add that outside of mathematics science does not work with proofs. As a general rule we eliminate hypotheses. For example one could assume that once faced with a give selective situation cells somehow respond in a Lamarckian way. However, as the actual mechanism (gene mutation) are happening before they face the selective situation it can be seen as highly unlikely. Moreover, we have quite a deep understanding of the biochemistry behind mutations and also the specific changes resulting in certain revertants (in case of auxotrophs) or resistances (and it is an almost trivial matter to sequence the DNA of mutants now to validate it).

 

In other words, the body of evidence strongly points towards unspecific mutations rather than adaptive responses. Note that there are also developmental effects in multicellular organisms, in which phenotypic variation is the result of complex signaling (internal and external) rather than on mutation.

[lordcheesehorn]

I see - I think.... So its something like this: the bacteria are artificially mutated. Let’s say there are ten bacteria and ten possible mutations a bacteria can have (I suppose there are millions, but for the sake of argument) and each bacteria has one of the ten. They are then placed in an environment which selects for the survival of one of the mutations (lets call it mutation x). The one that has that mutation x survives and the others die.

 

Is that it? Or something like it? If it is, I understand what you are saying, but I don’t see how this experiment rules out Lamarckian-influenced mutations in the wild... In the wild organisms do not always (or even ever?) move from one situation to a completely different situation with a set of genes to tackle the new situation, but exist in a changing context that they must change to adapt to. What rules out the hypothesis that, for example, a horse’s efforts to eat from taller and taller trees influences its gene mutations towards long-neck varieties?

 

I have another, far crazier hypothesis, but I’ll leave it here for now.

 

Many thanks for your time on this. One other thing, what do you think of this?

[CharonY]

The situation you describe is pretty close to what happens (there are some extra caveats, but I will it ignore it for now). The way to test this is simply by looking at a population of, say hundreds of cells and simply count whether the mutations are somewhat equally distributed. If they are, it indicates that under the given condition none of them are being selected. Put the same cells into a selective condition, you will see a massive change in frequencies (i.e. the beneficial ones will be suddenly dominant).

 

For the horse example it would require that its own DNA changes during its lifetime while eating from high leaves as opposed to eating low leaves (which can also be easily tested).

 

As for the plos paper, here the population of flies is kept under a given selective condition (i.e. dark) and again, the mechanism is that during these conditions there will be a shift towards beneficial traits.

 

What may confuse you is that these changes have to be viewed from a population perspective and results in changes of overall frequencies over several generations. If a horse feeds from a taller tree, its DNA does not change and its offspring will not have significant longer necks. However, if in a population of horses there are a few with longer necks, they will likely have more offspring and after a few generation you might see horses with longer necks. However, you can trace them back to those parents who originally had longer necks, as opposed to those with shorter necks but who fed on taller trees more frequently.

[lordcheesehorn]

I see... but I still can’t see how any of this rules out the hypothesis (or even significantly affects its unlikelihood) that the environment / context / phenotype is pushing (albeit gently) gene-mutation in one direction rather than another. How? How can we be sure, or sure enough? A lot seems to ride on this, for me at least.

 

(Many thanks again for your time. Late here. Have to go to bed now. Will pick this up later and hope you stick around for a day or three. This matter very important for me.)

Edited May 26, 2014 by lordcheesehorn

[John Cuthber]

"What is the solid evidence for random (meaning not epigenetic) causes for successful gene mutation?"

The evolution of epigenetics.

It's successful, and it logically predates epigenetics.

[chadn737]

1) "epigenetic" does not mean "the environment" or "caused by the environment".

 

2) We know that the environment does not cause specific mutations because we know that many, perhaps most mutations are either neutral or slightly deleterious in their effects. If the environment were inducing specific mutations and adaptations then we would expect a bias towards beneficial mutations.

 

3) We have identified the primary mechanisms by which mutations are induced and in thousands of mutation experiments in many different organisms, we know that these mutations are not determinative.

Edited May 26, 2014 by chadn737

[lordcheesehorn]

1) "epigenetic" does not mean "the environment" or "caused by the environment".

My mistake then. I thought it meant ‘non-genetic’ – meaning from the organism, the environment, martians, anything not the gene. What does it mean then?

2) We know that the environment does not cause specific mutations because we know that many, perhaps most mutations are either neutral or slightly deleterious in their effects

How do we know this? If its through lab-study, then perhaps the environment (a lab, rather than the vivid and complex wild) will not be having a positive influence? And how do we know that even with most mutations being either neutral or slightly deleterious in their effects the environment or the organism isn’t influencing the creation of the non-deletarious ones?

If the environment were inducing specific mutations and adaptations then we would expect a bias towards beneficial mutations.

Is this not what we find? In actual life, rather than in the lab?

3) We have identified the primary mechanisms by which mutations are induced and in thousands of mutation experiments in many different organisms, we know that these mutations are not determinative.

How have we ruled out that successful mutations in the wild aren’t influenced by the environment?

Thank you for your time. I’ll be back tomorrow. Hope you chaps are still here.

 

Edited May 27, 2014 by lordcheesehorn

[John Cuthber]

 

My mistake then. I thought it meant ‘non-genetic’ – meaning from the organism, the environment, martians, anything not the gene. What does it mean then?

Don't you think you should have checked what epigenetic meant before posting a thread about it?

 

Perhaps you would like to clarify what your original question was.

What are you seeking evidence for?

[lordcheesehorn]

Don't you think you should have checked what epigenetic meant before posting a thread about it?

My understanding was ‘resulting from external rather than genetic influences’ – that’s what the dictionary says, and that’s how I have always understood it. Not being a professional Biologist I am not surprised to find that my understanding is imperfect. If you are able to enlighten me as to my misuse of the term above (without, if possible, condescension), I would be most grateful.

 

I am seeking strong evidence that successful mutations in the wild are not influenced by the environment.

[chadn737]

My understanding was ‘resulting from external rather than genetic influences’ – that’s what the dictionary says, and that’s how I have always understood it. Not being a professional Biologist I am not surprised to find that my understanding is imperfect. If you are able to enlighten me as to my misuse of the term above (without, if possible, condescension), I would be most grateful.

 

I am seeking strong evidence that successful mutations in the wild are not influenced by the environment.

 

Which dictionary? I'd be very interested because it is wrong. "External" should not be part of the definition.

 

The original definition put forth by Waddington was before it was proven that DNA was the genetic material. He used it in reference as a "landscape" along which different paths could be taken to describe how genes could interact and to produce the phenotypes. It was very much a developmental theory. An important aspect of the definition, however, has always been its heritability through either meiosis or mitosis. This is also essential to the original developmental aspect of the definition because once a cell-type had determined its fate, it would pass on those traits to its daughter cells, even though genetically a heart cell is identical to a neuron. This definition therefore referred to a higher level of heritability. Later, when it was identified that certain traits were heritable through meiosis in certain species, despite no known genetic differences, the definition became more about transgenerational inheritance.

 

Several molecular mechanisms of epigenetic heritability are known, the two most prominent being DNA methylation and histone modification. Unfortunately, a lot of scientists outside of epigenetics confuse the mechanism as the phenomena of epigenetics itself. This is incorrect. DNA methylation and histone modifications can change dynamically in a cell and are not always inherited through mitosis and in animals very very rarely through meiosis. As heritability is key to the definition of epigenetics, non-heritable changes are not epigenetic. Because the environment can sometimes induce alterations of DNA methylation and histone modifications, many outside of epigenetics began to confuse the term to refer to any environmental interaction with the genome. However, that is simply a gene x environment interaction, something that has been known long before the term epigenetics was even coined. It is possible that such environmentally induced changes can be inherited, but very few examples have ever been conclusively demonstrated. Many true epigenetic variants, most of which are known in plants, are not environmentally induced at all, but due to random pertubations....similar to a mutation, hence why we call them epimutations.

 

Sorry to get off track, but the term epigenetics has become a buzz word leading to widespread abuse, especially amongst scientists who should know better.

[lordcheesehorn]

Thank you for this clarification. Kind of clarification, its a bit misty to me... what would you suggest as a pithy dictionary definition? Inheritance through either meiosis or mitosis (as opposed to what...?)?

 

The dictionary in question is the Oxford Shorter. Before you despair, words are famous for having multiple definitions. Could you explain why your definition is incompatible with the simpleton’s version?

 

And finally, you seem to know what you are on about, if you could find time to read through the thread, I’d love your view on the question I am (or have ended up) asking.

[chadn737]

Thank you for this clarification. Kind of clarification, its a bit misty to me... what would you suggest as a pithy dictionary definition? Inheritance through either meiosis or mitosis (as opposed to what...?)?

 

The dictionary in question is the Oxford Shorter. Before you despair, words are famous for having multiple definitions. Could you explain why your definition is incompatible with the simpleton’s version?

 

And finally, you seem to know what you are on about, if you could find time to read through the thread, I’d love your view on the question I am (or have ended up) asking.

 

I would suggest: "heritable variation through mitosis or meiosis that cannot be attributed to underlying genetic variation".

 

 

The dictionary definition confuses gene-expression with epigenetics. The two are not synonymous. Gene-expression changes can occur due to signaling and other factors and are not inherited. This is simply differential gene expression. Epigenetic effects typically affect gene expression, but are not limited to them nor is gene expression limited to epigenetics. Unfortunately, a lot of people, even biologists who know better get this confused. For example, prions, which affect phenotype through misfolding of proteins can be epigenetic and do not change gene expression.

Edited May 28, 2014 by chadn737

[lordcheesehorn]

So... Can anyone help?

I now understand how we might be able to rule out successful adaptations in the lab being caused by survival-selected random mutations, but how have we ruled this out in the wild?

What evidence is there that successful adaptations in the wild are due to random mutations and not through some mechanism (genetic or otherwise) that responds to the environment?

[Endy0816]

All the means by which DNA is changed are essentially known. It has some tricks but nothing to adapt it to a specific environment.

 

It generally doesn't want to to change if it can help it. You make changes and you are more likely to end up worse off than before.

 

Now other life can contribute in a positive fashion. Other life has undergone a selective bias and is composed of code that is functional if nothing else. That incorporation(in assorted forms) is a more useful effect in terms of progress. We have our mitochondria for example. Their incorporation was random, but leveraging the power of essentially parallel processing was a tremendous boon for both.

[lordcheesehorn]

Thank you. I understand this, but can you (or anyone) tell me what evidence there is that successful adaptations in the wild are due to random mutations and not through some mechanism (genetic or otherwise) that responds to the environment?

[Ophiolite]

To me it seems it largely the absence of any evidence to suggest that the environment does favour particular mutations. If this id occur one would expect to see some evidence for it. This seems to be lacking.

[lordcheesehorn]

One arguing that the environment influenced mutations would surely point to the extraordinary aptness of just about every living creature on earth for its particular situation.

[overtone]

Thank you. I understand this, but can you (or anyone) tell me what evidence there is that successful adaptations in the wild are due to random mutations and not through some mechanism (genetic or otherwise) that responds to the environment?

In the first place, that isn't so - many adaptations in the wild and in the lab and everywhere are due to physiological and biochemical responses to environment, from tanned skin and bigger muscles to thick fur and larger clutches of eggs. Some of these sequentially affect multiple generations, in part - nutritionally abetted larger size human babies tend to make larger size babies in their turn, regardless of genetics, for example.

 

But you seem to be referring to genetic inheritance only - the stuff that drives speciation and evolutionary change.

 

Two main lines of argument:

 

1) We know that "random" (properly understood) mutation with differential reproduction happens - we have thousands of examples of the results, can create more ourselves in the lab whenever we want to, have described several mechanisms for both production and control or management of such mutation, observed them individually and in combination both in the wild and in the lab, and so forth.

 

We know that in theory random mutation differentially reproduced can account for everything we have yet observed - nothing that cannot come into existence by such means has ever been observed.

 

We know that the patterns of evolutionary and contemporary structural relationship at all levels (from single cell organelles to continental scale ecological relationships), that is to say the observable consequences of whatever mechanisms have been in operation, structurally and mathematically (statistically) match the theoretical results of analysis based on random mutation with differential reproduction. Such analysis permeates all fields of biology and is completely standard to the point of assumption these days (example: http://en.wikipedia.org/wiki/Niche_apportionment_models http://en.wikipedia.org/wiki/Evolution_of_the_eye).

 

So: exists, is sufficient, agrees fully with observation, profitably guides research and grounds explanation. Line 1.

 

2) We have no evidence of any other cause of "successful" genetic change, at least not until recent genetic engineering advances provided us with the first known instances.

 

We have observed no adequate natural mechanism (the closest we get is the disabling of protective and repair mechanisms in certain bacteria when under stress, which allows an increase in the rate and proliferation of random mutations in certain areas of the bacterial genome).

 

We have observed none of the predicted patterns specific to environmentally guided genetic alteration. Very general and abstract theories based on the mere presence of such guidance, without even specifying a mechanism (and thus able to incorporate almost any), have been proposed and diligently investigated many times for hundreds of years now (varieties of Judeo-Christian Creationism, Lamarckian Evolution, etc) but have yet to acquire any support in evidence or in theoretical calculation; instead, they have proved to be unhelpful in suggesting research or predicting fruitful investigation, contradicted by the calculations of mathematical description, and in very poor agreement with field observation, at all appropriate scales. (The closest success so far that I know of was the use of the Gaia hypothesis to suggest research into homeostatic ecological management of key resources in the ocean - the discoveries there had few genetic implications afaik).

 

So: the alternatives do not yet exist, proposals disagree with observation so far, mislead research, and fail to plausibly explain anything Line 2

 

But you may want to check out the many variations on this theme - such as the Baldwin Effect (http://en.wikipedia.org/wiki/Baldwin_effect http://ase.tufts.edu/cogstud/dennett/papers/baldwincranefin.htm )

Edited June 19, 2014 by overtone

[chadn737]

In the first place, that isn't so - many adaptations in the wild and in the lab and everywhere are due to physiological and biochemical responses to environment, from tanned skin and bigger muscles to thick fur and larger clutches of eggs. Some of these sequentially affect multiple generations, in part - nutritionally abetted larger size human babies tend to make larger size babies in their turn, regardless of genetics, for example.

 

Can you provide an actual paper or data that supports the claim "nutritionally abetted larger size human babies tend to make larger size babies in their turn, regardless of genetics". I find this highly suspect, especially the assertion that they have eliminated genetics as a root cause.

 

If it is simply a matter that "nutritionally abetted" babies happen to live in an environment that provides such conditions and that that subsequent generations also live under such advantageous conditions, then this neither heritable nor adaptive. Its simply a result of positive environmental factors enabling a population to achieve its full genetic potential. The same can be said of clutch sizes.

 

Furthermore, physiological/biochemical changes are in no small part genetically determined. Some people tan easily, some do not tan at all given the same environmental exposure. This variation is genetic. When discussing gene x environment interactions, we must be careful not to confuse the effects of alleles as being static. Rather, particular alleles determine a range of potential phenotypes. No matter how much some people work out and diet, they will have an upper limit in their ability to develop muscle mass. The genetics of another person, however, may enable them to achieve greater muscle mass than someone else, a potential that is genetic, but realized only under certain environmental conditions.

[CharonY]

 

Can you provide an actual paper or data that supports the claim "nutritionally abetted larger size human babies tend to make larger size babies in their turn, regardless of genetics". I find this highly suspect, especially the assertion that they have eliminated genetics as a root cause.

 

If it is simply a matter that "nutritionally abetted" babies happen to live in an environment that provides such conditions and that that subsequent generations also live under such advantageous conditions, then this neither heritable nor adaptive. Its simply a result of positive environmental factors enabling a population to achieve its full genetic potential. The same can be said of clutch sizes.

 

 

Well in that particular case nutritional variation is likely to be more responsible for physiological outcomes than genetic variation. In that narrow sense both statements are not mutually exclusive.

 

To be more precise, there are studies that indicate that mother's with low birth weight also often have children with low birthweight and higher mortality. Of course genetics plays a role to some extent, but some of the studies indicate that malnutrition as fetus (or child) can reduce their ability to nourish their own kids in utero.

However, above a certain birthweight the correlation goes away. I.e. the stated positive correlation

 

"nutritionally abetted larger size human babies tend to make larger size babies in their turn, regardless of genetics"

 

appears not to be substantiated by data. In that group chadn737's point is more relevant, i.e. nutrition is sufficiently high and variation are more likely to be explained by genetics.

 

Edit: on reflection I may have just reworded chad's argument. Blame the lack of coffee. Also the typos. And grammar.

Edited June 19, 2014 by CharonY

[chadn737]

 

Well in that particular case nutritional variation is likely to be more responsible for physiological outcomes than genetic variation. In that narrow sense both statements are not mutually exclusive.

 

To be more precise, there are studies that indicate that mother's with low birth weight also often have children with low birthweight and higher mortality. Of course genetics plays a role to some extent, but some of the studies indicate that malnutrition as fetus (or child) can reduce their ability to nourish their own kids in utero.

However, above a certain birthweight the correlation goes away. I.e. the stated positive correlation

 

appears not to be substantiated by data. In that group chadn737's point is more relevant, i.e. nutrition is sufficiently high and variation are more likely to be explained by genetics.

 

Edit: on reflection I may have just reworded chad's argument. Blame the lack of coffee. Also the typos. And grammar.

 

The transgenerational effects of low birth weight I think may be one of the few cases of actual transgenerational epigenetics in mammals that has held up to any degree. Although its very hard to rule out the effects of genetics. Even in homozygous selfing plants, many assumed "epigenetic" effects have turned out to be in reality genetic. It becomes much harder to rule this possibility out with mammals where selfing is impossible, making maintaining homozygosity very difficult. The other problem I have is that the transgenerational effects of low birth rate is not really adaptive as far as I can tell....at least its not beneficial in any sense. Not trying to debate with you on this, the point I'm trying to make is that while these would be non-random, they are not beneficial in the sense that natural selection would favor these effects and therefore maintain them.

[lordcheesehorn]

Overtone: thank you for your long answer.

 

Line one. Chaos theory, as far as I understand it, often describes systems comprised of many individual elements which seem to be behaving randomly, and yet, as a whole, or viewed from a different perspective, exhibit some kind of order. Can you explain how you have ruled out any kind of order in mutating genes or any kind of environmental influence?

 

Line two. I am intrigued about ‘recent genetic engineering advances [that have] provided us with the first known instances [of “successful” genetic change]’. Can you elaborate?

 

Also, you say you ‘have observed none of the predicted patterns specific to environmentally guided genetic alteration.’ Is not the outstanding appropriateness of just about every organism to its environment a sufficiently compelling reason to assume that the environment has some impact on genetic evolution?

 

From what you say, I gather that we have not ruled out some means for the environment to influence mutations.

 

I am not suggesting that there are no such things as random mutations. What I am endeavouring to understand is if the environment might have some means of influencing genes, or if cells might have some means of genetically responding to the environment. I gather that science has not found such a mechanism, but I am also starting to think it has definitely not ruled out that it might be there.

 

All further thoughts welcome.

Edited June 20, 2014 by lordcheesehorn