DNA is not just a static read-only memory (ROM) for coding proteins, but hosts dynamic random access memory (RAM) in the form of methylations and histone modifications for regulation of gene expression, cellular differentiation, learning and cognition, and who knows what else. The picture below depicts how rapidly the RAM aspect of DNA is changed during embryogenesis.
Many of the DNA methylation patterns are in non-coding repetitive regions. This suggests at least some of the roles of non-coding DNA are involved in supporting the complex epignomic memory in each cell.
Depicted below are changes in epigenetic methylation marks on the DNA in the stages of embryo development. The light green colors indicate epigenetic methylations and the darker blue colors indicate absence of epigenetic methylations. In boxes “a” through “l”, the bottom part is the DNA from the mother and the top part is the DNA from the father. Eventually the DNA from mom and dad mix in the 4 cells of box “m”.
Note how the epigenetic marks are erased from the parternal DNA first!
The depiction below shows how rapidly epigenetic changes happen even in time frames as short as hours. Each cell has a slightly different methylation pattern and hence each cell’s RAM has some unique information. If we consider that the human has 100 trillion cells and that each cell has 30 million potential methylation sites, the sum total of RAM memory implemented by epigenetic cytosine methylation alone is on the order of sextillions of bits of Shannon information. Like histones, DNA methylations can be written, erased and read.
When scientists inhibit epigenetic changes, the results are usually lethal. So we know the epigenetic component of the DNA is vital to life.
a–e, Anti-5-methylcytosine (MeC) immunofluorescence of mouse one-cell embryos. a, Zygote 3 h after fertilization with intense MeC labelling of both pronuclei (>10). Numbers in parentheses indicate the number of embryos analysed. b Paternal and maternal pronuclei at 6 h (>10). c, Undermethylated paternal pronucleus at 8 h (>20). The smaller female pronucleus remains methylated. d, Aphidicolin-treated one-cell embryo displaying demethylation of the male pronucleus (>20). e, First metaphase (>5). f–j, Controls. Anti-DNA immunofluorescence of one-cell embryos demonstrates that both chromatin sets are accessible to antibody molecules. f, 3 h (>5). g, 6 h (>5). h, 8 h (>5). i, Aphidicolin treatment (>5). j, First metaphase (2). k,l, MeC staining of two-cell embryos at 22 h (>20) (k) and 32 h (>20) (l) shows that the paternal and maternal compartments have different methylation levels. m, Four-cell embryo at 45 h (>10). The MeC-staining intensity of the maternal half of the nucleus is weaker than in two-cell embryos. Scale bar, 10 mum.
http://www.nature.com/nature/journal/v403/n6769/fig_tab/403501b0_F1.html#figure-title
http://www.nature.com/nature/journal/v403/n6769/fig_tab/403501b0_ft.html
Some literature counts X-chromosome inactivation as “imprinting”. Some interesting facts:
https://en.wikipedia.org/wiki/X-inactivation
Below is an incredible photo of the epigenetically imprinted Xi (inactivated X chromosome) and the non-epigentically-imprinted Xa (activated X-chromosome).
This raises the question, how did the Xist lncRNA evolve to do it’s wonderful work? lncRNA may or may not have been classified as junk at one time since they are non-coding, but Xist like HOTAIR lncRNAs are examples of non-coding RNAs that are confirmed to definitely not be junk.
Allan Miller,
Hi Allan,
I never did buy the Genetic Conflict Hypothesis as proposed in the Igf2r story
Here is the story from one of Sal’s preferred links:
It turns out that many imprinted genes are involved in growth and metabolism. Paternal imprinting favors the production of larger offspring, and maternal imprinting favors smaller offspring. Often maternally and paternally imprinted genes work in the very same growth pathways. This conflict of interest sets up an epigenetic battle between the parents — a sort of parental tug-of-war. http://learn.genetics.utah.edu/content/epigenetics/imprinting/
Like I said, this interpretation doesn’t make sense to me, the mother’s dilemma is quickly resolved by erasure of father’s marks and resetting to the maternal setting. Of course, completely silencing the father’s allele would then be equivalent to knockout of the father’s allele which should produce overly small offspring. The easiest evolutionary fix would be selection for some Goldilocks allele that produces optimally sized offspring.
I think something else is going on here that indicates cryptic physiological complexity at a higher level.
The differential methylation states of the two closely placed Igf2r upsteam/downstream promoters, the later producing an antisense RNA sounds uncannily like Mark Ptashne’s story.
http://www.pnas.org/content/110/18/7101.full#ref-1
Back to λ bacteriophage cI proteins: As in the Trp operon, “Autogenous regulation” again occurs such that the prophage dictates the synthesis of a low level of cI repressor protein binding to a promoter site called PRM (Promoter for Repressor Maintenance).
This where it gets tricky: cI protein is simultaneously a repressor in one DNA direction as well as transcription activator on the same stretch of DNA, but in the other direction.
While the cI protein is activating expression of its own gene (a positive feedback reaction) it is simultaneously repressing transcription of viral genes to the right (including the cII gene that initiated cI’s expression to begin with). Ptashne is correctly citing an example of gene regulation that simultaneously demonstrates repressible gene regulation (lysogeny), inducible gene regulation (lysis) and positive feedback (cI autogenous regulation). (BTW, cI also prevents superinfection by any λ virus that happens to enter a cell already possessing a propage – neat or what?!)
(Aside Quick question: If positive feedback is occurring, why do cl levels not rise until the entire cell fills up with cI protein? Ans: that’s where cII comes into play: Overshoots of cI supress expression of cII which in turn lowers levels of cI.)
Ptashne nailed it! Classical Geneticists have known for decades that there exist gene regulatory models where Positive Feedback control in fact maintains homeostasis, if by homeostasis we understand “status quo”! It gets better: irreversible commitment points often occur in Biology. Self-perpetuating responses are then required long after the triggering stimulus is removed and these responses occur as a result of positive feedback as well as double-negative feedback mechanisms as first described by Jacob and Monod. http://tinyurl.com/pqx4jom
James Ferrell does an excellent job of elucidating these difficult concepts.
http://www.medicine.mcgill.ca/physio/mackeylab/courses_mackey/pdf_files/ferrell_2002.pdf
Quick google whacks confirm that the epigenetics story includes trans-factors which interact with the allele discriminating signal, which only makes sense given one Igf2r promoter vs another needs to be somehow identified during differential methylation. Again, methylation is the result not the cause of epigenetic signaling.
Ptashne’s frustration is palpable… exasperation actually. I can relate. Recent advances in technology have given rise to a whole new generation of “DNA–chompers” who have had little, if any, training in classical genetics. We are essentially reinventing the wheel! According to Ptashne, this younger generation of DNA-chompers would not be getting some of their “facts” wrong (in this case the Epigenetics story) if only they paid better attention to the work of their predecessors.
FTR – The Överkalix study was confirmed by the Dutch Winter Hunger study.
Here is what I think is really happening with those few genes that seem to exhibit “epigenetics” with the relatively few imprinted genes involved in growth and metabolism:
advocatus diaboli ON:
According to some, the thrifty phenotype hypothesis suggests that early-life metabolic adaptations help in survival of the organism by selecting an appropriate trajectory of growth in response to environmental cues. That means phenotypic change in response to the environment generate epigenetic changes that prepares a population of adult organisms for better survival in the long term and (this is the important bit) these changes are heritable from one generation to the next. In other words,
Epigenetic’s impact on Evolutionary theory could be very important… but only when considering selection in hierarchical terms. (i,e. Multi-Level Selection)
That idea is mind-boggling… in other words Novo-Lamarckism (not Lamarckism,not Neo-Lamarkism) would be back in vogue. (Or as Doolittle & Maderspacher phrased it: “New Lysenkoism”)
In Darwinian terms – isolated individual variants are not always grist enough for Natural Selection’s mill, rather entire populations can present a “tentative” new phenotype (presenting greater opportunity for mutation the old fashioned way) in response to environmental change that can subsequently respond to Natural Selection by altering gene regulation for the long term. OOPs – so sorry – My German predilection for run-on sentences is showing again!
ITMT
(Yikes: Incoming! Baton down the hatches, Was that epigenetics as a putative mechanism for “group selection”?!)
Explained another way: some populations have a thrifty phenotype as a default setting – other populations have a spendthrift phenotype as a default setting. Default settings can be switched on and off in response to the environment and these switches are heritable. Eventually populations can change their default settings in response to Natural Selection.
advocatus diaboli OFF
Is this really epigenetics? I dunno… even so, it seems to me any such phenomenon would be limited to a very small repertoire of genes restricted to growth and nutrition.
Of course, the very mention epigenetics and selection in the same breath raises emphatic objections by some… check out this thread:
http://sandwalk.blogspot.ca/2014/03/what-is-epigenetics.html
bringing me back to Gould’s proposal of selection in hierarchical terms. (i,e. Multi-Level Selection)
LoL. Well, I am no fan of Salvador and make no bones about it, which is why he has me on ignore. If that gives a hint.
Mung,
It’s OK, I didn’t need a hint. Your intent was clear; I was being ironic.
TomMueller,
That is not the only way to resolve the dilemma. An oppositely imprinted gene can have an antagonistic effect and achieve the same result. I think it better to think from each locus’s perspective than the diploid’s. ‘The mother’ is not in control of anything; she is a diploid gene vehicle (in Dawkinsian terms) in which some of the action takes place. There are many imprinted loci. Some loci in her may spread if they perform the task of wiping paternal imprints. But she has sons, and ‘wants’ them to be furnished with an optimal strategy too. Really, it’s just autosomal genes at one locus interacting with those at another, in the complex arena of serial dioecious bodies. A gene that maintains a particular imprint may spread. But if it distorts the sex ratio, because females are fitter than males (say), Fisher comes into play and selects for an antagonostc effect.
Any advantage to suppression of paternal expression is countered by disadvantage when those same suppressive genes are carried unexpressed in males. And, of course, there is strong linkage due to imprinted genes occurring in blocks – imprints huddle together, where divided they may fall. The net result is a perpetual no-win tussle.
I would urge you to read the Imprinting chapter in Burt and Trivers’ Genomes in Conflict (a book I often mention; it is a gleeful menagerie of departures from adaptive/stochastic explanations as being the only games in town).
TomMueller,
I’d be happier if I could even see the barest hope of a mechanism. I realise phenomenon comes first, but I’m not even convinced we have the phenomenon. The Swedish cohort involved about 300 individuals and their descendants. Is that enough? How many random associations could be made out of that data with the same confidence levels or better?
It just seems a preposterous idea, that of your four grandparents you could adopt a particular epigenetic state in certain metabolic genes from the one who went hungry 50 years back. And that a somatic epigenetic change in a limited set of genes with tissue-specific expression could find its way into the germline. And that this could be any kind of plausible adaptation, driven by significantly regular famine.
stcordova,
Quite.
I think enormous confusion arises (as we have seen) when you use a term like ‘transgenerational epigenetic inheritance’ when you mean the genetic inheritance of the genes that control development. The fact that DNA can act as both source and substrate for gene action seems to get people unreasonably excited about some kind of paradigm shift.
Still all ‘just genes’ though. Still waiting for multigenerational inheritance via a medium other than unmethylated nucleic acid and ‘zygote state’ chromatin (a state established by genes).
Allan Miller,
Jeez. My proof reading is getting wors.
stcordova,
I wouldn’t disagree. Since imprinting involves expression in a parent-of-origin manner, inactivation of either X results in parent-of-origin silencing, as an unavoidable byproduct. Initially stochastic, it provides a means by which strategies can emerge to favour one parent or the other, with corresponding reaction by other genes on the X through sex ratio.
This may actually be relevant to the origin of imprinting as a whole. The XY system in higher mammals may have been the first to give parent-of-origin distinction. It’s initially passive, an inevitable consequence of dosage reduction. From there, imprinting mechanisms could spread to autosomes.
How did Xist lncRNA evolve? Depends if you think evolution happened at all, but it appears to come from a protein coding gene, not any other kind of junk. Presumably a pseudogene though. This is the thing: the designation ‘junk’ is always provisional and not necessarily permanent. There is obviously no conflict between exaptation of nonfunctional sequence and the existence of nonfunctional sequence.
Hi Allan
I just want to preface my response by thanking you (and others) for helping an aging and hopelessly noncurrent teacher and bringing me up to speed.
Allan, the fact that many if not all of these imprinted genes are involved in growth and metabolism rings loudly seems to be significant to my way of thinking.
I did a quick google-whack to ensure my memory wasn’t playing tricks on me. Here is a quick reference summarizing what I am on about:
https://en.wikipedia.org/wiki/Thrifty_gene_hypothesis
There seem to be several versions of events starting the “Thrifty Gene Hypothesis” on to the “Thrifty Genotype Hypothesis” continuing with the “Thrifty Phenotype Hypothesis” and my favorite so far “The Thrifty Epigenomic Hypothesis”.
I remind you that you and I already discussed this in some detail on an earlier occasion: http://tinyurl.com/zxpmrrm
ITMT – the Överkalix Study was confirmed by the Dutch Winter Famine Study which was also confirmed by the Israeli Holocaust Survivor Study… plus other studies apparently. Where there is smoke there is fire.
Re: I’d be happier if I could even see the barest hope of a mechanism.
Ptashne I think rises to the challenge. I invite you to reread my purple prose above.
Specifically
… commitment points often occur in Biology. Self-perpetuating responses are then required long after the triggering stimulus is removed and these responses occur as a result of positive feedback as well as double-negative feedback mechanisms as first described by Jacob and Monod. http://tinyurl.com/pqx4jom
James Ferrell does an excellent job of elucidating these difficult concepts.
http://www.medicine.mcgill.ca/physio/mackeylab/courses_mackey/pdf_files/ferrell_2002.pdf
Quick google whacks confirm that the epigenetics story includes trans-factors which interact with the allele discriminating signal, which only makes sense given one Igf2r promoter vs another needs to be somehow identified during differential methylation. Again, methylation is the result not the cause of epigenetic signaling.
Earlier you said
That is not the only way to resolve the dilemma. An oppositely imprinted gene can have an antagonistic effect and achieve the same result. I think it better to think from each locus’s perspective than the diploid’s. ‘The mother’ is not in control of anything; she is a diploid gene vehicle (in Dawkinsian terms) in which some of the action takes place.
I think you (and Dawkins) are taking a far too DNA-centric/chromosome POV! The mother can exert control by her overwhelming contribution of cytoplasm to the zygote. Now think trans-acting control of λ lysogeny.
Finally, there are plenty of examples in Biology where Fisher’s rule can be TEMPORARILY abrogated, I am specifically thinking specifically Ichneumon wasps as my particular favorite example. But I do not want to digress down those lines just yet.
Hi Allan
This has got to be one of your most insightful posts yet!
I refer you to an interesting post by Georgi
http://tinyurl.com/jk7flrx
I am still wrapping my head around these two papers:
http://genesdev.cshlp.org/content/30/2/191.full
http://gbe.oxfordjournals.org/content/early/2015/08/06/gbe.evv152.full.pdf
best
Amazingly this discussion for the most part hasn’t devolved into a discussion of creation vs. evolution, but of how to characterize biochemical mechanisms of inheritance or lack thereof. Hence it has been one of the more productive discussion for me personally as I have assignments related to the diagrams and concepts I’ve shared in this discussion. I actually have 2 exams and 1 assignment due in not too long!
I’m taking a biochemistry class, and my lack of having undergrad Organic Chem has thankfully not been a hindrance since a lot of the biochem learning is more like memorizing a phone book — lists of chemicals and their roles. I mentioned some here: Xist, DMNT1, DMNT3. The peer-reviewed literature also almost reads like a phone book.
The classes hardly focus on the question of origins but rather structural and chemical relationships and the landmark experiments and experimental techniques to discover these relationships.
The photo in the OP is a rather amazing laboratory technique as well as the RNA Fish technique showing the Xist lncRNA bathing the Xi chromosome. Lately, I find the study of such experimental explorations exhilarating compared to the repetitive discussion about ID vs. evolution. The ingenuity of the scientists in constructing the experiments is breath taking.
Personally, I’ve been surprised how much blotting (Northern and Western blotting) is still used in the present day to make various inferences about molecular structure. Occasionally we are lucky enough to have microscopy experiments and mass spectrometry that confirm the inferences of the blotting techniques. This was very evident in the question of histone modifications. The set of agonizing experiments that elucidate our current knowledge spans decades, and in the case of chromatin, over a century.
There is almost definitely trangenerational epigenetic inheritance as evidenced by genetically clonal mice that have differing traits. The photo below are of genetically clonal mice with different epigenetic marks.
I am not a gene-centrist, I’m a holistic-centrist as far as mechanisms of heritable information. DNA from a mammary gland in Dolly is identical to the DNA in the Zygote of the clone made from the mammary-gland DNA, therefore the DNA doesn’t contain all the necessary information to create a fully functional sheep.
The Cytoplasm has information and technology that is not contained in the DNA, not the least of which is the developmental program. Imho, DNA contains necessary but not sufficient information to create an organism. How that heritable information is represented and stored and then used is not well understood.
TomMueller,
I think you are taking a far too un-DNA-centric a view! Don’t forget the mother’s cytoplasm is made from both her paternal and maternal genes, and she also has sons.
You have to, at some stage, think how a locus actually gets fixed in a recombining population. Loci spread reasonably independently, largely by selection/drift, but to some extent by distortion of Mendelian 50/50 ratios. The dynamics of this last are best understood at locus level IMO. They often have no overall fitness effect on organisms, simply distorting transmission on their own account.
A locus having an effect only in male diploids can become common by distorting resources towards its primary vehicles. Total offspring may stay the same, but frequencies shift from 50%. As such an allele is not even expressed in females, it makes no contribution to fitness there. But by increasing the proportion of males born, then it may spread by a form of drive.
How is ‘the female’ to respond? Where is ‘she’ even located, genetically? All you have is a succession of allele copies. The male-favouring gene has the long term effect of putting a premium on female offspring. Thus any gene that can oppose the tendency towards asymmetry will increase its own representation by producng more of the ‘premium’ sex. The long term is a succession of distortions and returns to the mean.
But to assume that the response of the female WOULD be (if paternal drive were the primary cause) to erase all paternal imprints is to assume that the first thing that comes up in evolution will be the first thing you thought of. The non-reboot of paternal imprints following erasure is certainly possible. But so are a whole host of other potential genetic responses. Wiping the entire genome is rather coarse-grained, may cause pleiotropic effects, or may simply not evolve first. Whereas a simple female-imprinted antagonist of the original male-booster targets the problem precisely. I find that more likely, and it has the handy benefit of consistency with the imprinted gene data, which does form numerous otherwise inexplicable antagonistic pairs.
It’s all very well looking at things from the perspective of a female and saying what ‘she should do’. But ‘she’ can’t do anything on the evolutionary stage. ‘She’ does not even exist every generation – females only come up 50% of the time.
Kin selection theory successfully explains much about the nature of the imprinted genes, their main tissues of expression, their phylogenetic distribution. The main objection seems to be not being a fan of gene-centrism! And hence, ironically, hoping for refuge in adaptationism.
There is a bit of unstated circular inference in that claim. One could just as well say the mother’s cytoplasm is made from the combined cytoplasms and DNA of the sperm (what little cytoplasm it has) and egg.
The way to demonstrate DNA is not central is to show that we can have the same DNA in different cells but the cells develop differently despite having identical DNA. I think that is painfully in evidence. Cytoplasm has a slight priority over DNA — enucleated cells can develop to the blastula stage (presumably because of front loaded mRNAs floating around).
Neither the DNA, RNA, Cytoplasm are central — the system is best understood in terms of holism. Unfortunately, we understand DNA far better than the information processing and storage in the cytoplasm. Hence we collectively tend to resort to explanations based on our current limited set of knowledge even if those explanations could be very much wrong in the end.
stcordova,
Rubbish. It is merely a counter to the supposition that ‘a female’ is a distinct evolutionary entity with long-term interests. I was saying that autosomes are not gendered. It was not about DNA vs cytoplasm, but the ‘gender’ issue.
One could say that, but one would be missing the point. Tom was specifically talking of the volume issue, and its origin in ‘the female’.
Jeez. And what contribution to long-term evolutionary arguments do these things make? Stab someone and they don’t die instantly, so blood isn’t all it’s cracked up to be.
We are talking on completely different scales. I am talking of the evolutionary scale – a scale your apparent blind-spot has trouble even comprehending exists, let alone allowing you to sensibly evaluate claims re: processes that operate on those scales.
What’s the Holistic Theory of genomic imprinting?
No Theory Allowed ‘cos it might be wrong. Riiight.
How would your worldview survive a realisation that Mendelian genetics is indeed all there is to long-term inheritance? I don’t know why Creationists seize upon this kind of stuff so passionately, and refuse to consider all counter-arguments. There IS a new paradigm! There is, there is!
I’m not seeing it. So far, I’m seeing hype. Epigenetics is real and interesting, but has bog all to do with the medium of long term inheritance.
stcordova,
I think you’ll find that program ultimately resides in the DNA. That’s how Dolly was cloned. Just because Dolly did not develop into a massive mammary gland … !
Nah, we’ll find it in the glycan complexes in the cytoplasm. 🙂
stcordova,
That would be very easy to test. I wonder why no-one noticed yet?
But wait – where does glycan come from?
For interested readers:
http://www.sciencedirect.com/science/article/pii/S0304416515002883
Glycans, baby, glycans! DNA is so 20th century. 🙂
stcordova,
Any theory will do, as long as it’s not the current one.
From a combination of other glycans and other stuff in the cell. Like I said, cytoplasms without DNA can copy themselves except for the mRNAs, but it’s got everything else.
In contrast, as strand of DNA by itself can’t copy itself. Thus, this shows the cytoplasm has more information in it than DNA.
“knock out” cytoplasm of a cell and you don’t have anything. Cytoplasm is essential for inheritance.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365393/
stcordova,
Why, thanks professor! Not finished the biochemistry module yet, then.
Copied cytoplasm. Sure.
Huh? That, your suggestion that cytoplasm copies itself but DNA doesn’t, and that this non-fact proves there is more ‘info’ in the former, has to be the densest thing I’ve seen for a long time. Congratulations!
Which is precisely why DNA wraps itself up in it. For this generation and the next. It is being made continually.
stcordova,
Are you bolding the bits you don’t understand? Nope, DNA nothing to do with glycans. No sirree! And glycans are inherited independently of DNA for ___ generations.
Here’s the game: I say “over the long term, DNA is the sole medium of inheritance”.
Pause, then
“here’s something that acts over the short term, in 1 individual or a parent-child sequence, which blows your contention out of the water”.
If your chosen refutation does not go beyond 1 generation, it is not a refutation. Though I have been waiting for membranes to come up.
Epigenetic regulation of glycosylation is the quantum mechanics of biology
http://www.sciencedirect.com/science/article/pii/S0304416513003619
Allan,
I’m just trying to expand your horizons from a gene-centric viewpoint of inheritance and thus evolution.
“Micro evolution via selection acting on epimutations in the glycome vs. mutations in the genome. ”
One can still be an evolutionist without being a gene-centrist.
stcordova,
It’s a new paradigm! Praise be!
You aren’t telling me anything I don’t know about the relationship between gene and cytoplasm. I am arguing gene-centrism in the specific case of imprinting. It is the only explanation I am aware of that makes sense. Tom was doubtful, so I attempted to sell it.
Don’t assume, because I can adopt a gene-centric stance, that this is the only way I can view biology. It is necessary to take a pluralistic approach, and adopt the stance that works best. Patting oneself on the back for the apparent rational superiority of ‘holism’ is actually narrowing your view, ironically, because you think reductionist approaches hold no merit. You won’t even consider gene centrism, and argue against it at every opportunity. Nonetheless, every proposed alternative candidate turns out to have genes at the levers.
Why would one discard it? One understands biology better if one has an open mind to ALL its facets.
Genetic conflict is a vital factor in the dynamic of sexual reproduction. It is not well explained by invoking cytoplasmic factors or considering matters from the point of view of whole organisms. It is well explained considering the genetic level, and its evolutionary dynamic.
A quick drive-by, as I have been busy elsewhere…
Also, at very high concentrations of repressor, repressor will occupy Or3, thereby inhibiting its own synthesis, per Ptashne.
lambda rocks!
Sal answers a question:
LOL.
Sal sez:
I agree, in that its something that neophytes can gleefully misinterpret. Good point, Sal.
In case you are wondering Sal, I still agree with Allan 100%.
DNA_jock said:
If you bothered clicking on the link, that was actually the title of the linked article.
Hang on there, where have I ever said that! That’s you attributing ideas again to me that I don’t hold.
The mechanisms of inheritance reduces to many parts of the cell, not just the DNA.
The interactome of the parent cell serves as a heritable template for the daughter cells. It’s not the DNA that serves as a template:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3302650/
Put a frog in a blender. You have all the proteins in the right proportions just as the DNA would supposedly code for them and (generously supposing) regulate the proportions. But proteins by themselves in the right proportions do not a functioning frog make.
That cytoplasmic template includes the posttranslational modifications that make the 1 million or more proteins from 20,000 genes through alternative splicing plus post translational modification.
stcordova,
Says the man who thinks I need to stop being solely gene-centric as if I ever was.
It’s not something you have said explicitly, it is there in everything you write. I was talking particularly about gene-centrism as an evolutionary position. You think it holds no merit. And that appears to be because, while you can conceptualise development, you seem incapable of conceptualising evolution. Your constant countering of evolutionary arguments with developmental examples shows that.
See, there you go again. Different scales, different systems.
Me: “DNA is the sole long term medium of inheritance”
Sal “It isn’t because cytoplasmic factors …”.
Two different things. Cytoplasmic factors last a couple of generations at best
But even so, the proteins in the cytoplasm come from DNA. DNA’s epigenetic state is set by factors that come from DNA. A cyclic epigenetic state is possible only because of the constancy provided by DNA sequence, as the cytoplasm (and the DNA epigenetic state) whirrs through its changes. Cytoplasm is continually replenished. From the DNA, whose sequence is a constant source.
Yes, of course DNA is acted upon by cytoplasmic content as well as manufacturing it. This seems to bamboozle the hell out of people. I can hear the ‘gotcha’ cry: “DNA makes nothing! It needs polymerases!”. Sigh.
Perhaps to make sense of why I’m interested in the cytoplasm being a template for the next generation, let me explain.
I think if things like the interactome serve as a template for the cells in a species, that means for there to be macro evolution, not only must there be changes in the DNA but simulatneous sweeping changes in the cytoplasm. Hence the evolutionary change from prokaryote to eukaryote would be indistinguishable from a miracle.
Not only is the DNA structure different from prokaryote to eukaryote, the cytoplasmic structure had to undergo simultaneous change. But such changes are statistically indistinguishable from miracles. Ergo, God (or something with an equivalent skill set), ergo God did it.
That’s why the necessity of non-genetic inheritance is of interest to me. I take it as indirect evidence that Universal Common Ancestry would require sets of events indistinguishable from miracles.
stcordova,
As far as endosymbiosis is concerned, all you need is compartmentalisation. If an endosymbiont brings its own membrane, you have nested cytoplasm. Each chromosome is surrounded by its own products, same as when they were separate. Gradually, the two system merge, albeit incompletely, mainly by genes migrating from endosymbiont to nucleus. But everything does not need to happen at once. There is time for tuning. Think Wolbachia.
Hi Allan
I think you are misconstruing what I was attempting to say.
Again, I remind you we touched on this already elsewhere: http://tinyurl.com/zxpmrrm
Presume there are two metabolic default settings: feast-mode vs famine-mode where famine-mode is deleterious in times of plenty while the converse is also true.
Phenotypic change in response to the environment generates so-called epigenetic changes that prepares a population of adult organisms for better survival in the SHORT term and (this is the important bit) these changes are “heritable” from one generation to the next.
This is where we are talking at cross-purposes. “Heritable” is not really correct. “Temporarily transferable phenotype” is more like it. That is why “Epigenetic” is hyphenated; “Epigenetic” really is NOT genetic.
In Darwinian terms – isolated individual variants are not always grist enough for Natural Selection’s mill, rather entire populations reacting to some environmental trigger can present a “tentative” new phenotype (presenting greater opportunity for mutation the old fashioned way). A temporary change in phenotype preceded any Natural Selection altering gene regulation for the long term.
Let’s try it again from another angle:
If environmental stresses are transitory and frequent, the ideal scenario would be some reactive mechanism that permits transitory toggling back and forth between “default settings”. In other words, transitory epigenetic memory (that decays with a half-life of 1-3 generations) would be in itself an adaptation subject to natural selection. Meta-selection as it were.
What I am trying to say is that the very possession of a « toggle-switch » is in itself an adaptation that is genetically inherited (yes – I agree with you there) but the pseudo-memory effects observed thereby are not “genetic” in the true sense of the word. We need to sort out some word usage and parse our terms carefully.
I will stop there, before continuing – I just want to see if you are on board so far or whether I have made a complete hash of things and publically embarrassed myself yet again.
TomMueller,
Yes, I agree there is certainly some potential for cross-talk.
I think I get your drift. My skepticism arises through the (to me) unlikely scenario of fluctuating food supply being a sufficient driver for the establishment of an adaptive ‘toggle’ mechanism in the genome. Where lineages experience fluctuating food supply, there is clearly an opportunity for genes that deal better with that fluctuation. We get exactly that with seasonal fluctuations. But the key there is that is a very regular, and reasonably short term, cycle.
The general thing with adaptation is that it must track environmental consistency. (In this case, the ‘consistency’ is actually a consistent inconsistency – the genes we are hypothesising are dealing better with both parts of the feast/famine cycle.). But the fluctuations we are looking at are on quite a large scale. And, in fact, if the response is to act between parent and child (or even, by magic 😉 , grandparent and grandchild), you need conditions to last a while, which lengthens the period even more – the ‘toggle’ is supposed to be adaptive because children typically experience the same conditions as their parents.
I’d like to see a pop-genetic treatment. Well, I wouldn’t because I probably wouldn’t understand it(!), but I think it should be subject to one. In the case of the ‘fluctuating environment’ theory of sex (variant offspring hedge the parents’ bets) it was found that the environment would need to fluctuate every generation.
Let’s not forget that we’d need several components to this system – detection of general nutrition directing the setting of the switch in the germ line, the switch itself, an effect of the setting of the toggle on development. And we have two (or four) genomes’ experiences to choose from in setting the switch.
TomMueller,
Yes, rereading the same may be true of you. The post you excerpted was related to the ‘gene-centric’ view of gender-asymmetric tussles over gene expression, but your discussion related to the ‘Hunger’ studies.
The arena of contest under the kin selection theory of imprinting is mother vs foetus; that of your adaptive ‘toggle’ is the individual and its offspring vs the environment. I was not addressing the hunger studies (which I think have too small a cohort size to be conclusive).
Hi Allan
regarding cohort size:
As I mentioned before, the Swedish studies have been confirmed by the Dutch Winter Hunger Studies which have been confirmed by the Israeli Holocaust Survivor studies.
I suggest where there is smoke there is fire.
ITMT – Steatopygia of the San people of the Kalahari seems to me to be a classic paradigm of an extreme version of what we are talking about.
On the subject of “gender”:
ITMT, I am intrigued with the suggestion by some German researchers that homosexuality may be an epigenetic phenomenon related to in utero stress.
Finally your citation of Fisher’s principle has many known exceptions in Biology, my favorite being the haplodiploidy of Ichneumon wasps (flies actually)
When conditions are good – meiosis is essentially a means of asexual cloning via serial inbred brother-sister mating. Neat or what?
Allan Miller,
Hi again Allan
re: And, in fact, if the response is to act between parent and child (or even, by magic 😉 , grandparent and grandchild), you need conditions to last a while, which lengthens the period even more – the ‘toggle’ is supposed to be adaptive because children typically experience the same conditions as their parents.
Exactly.
Meaning this whole discussion of Epigenetics may be decidedly UNprofound!
Perhaps much of what we are discussing is conflation with already well understood “Maternal Patterning” (for lack of a better term just now) in the Egg Cytoplasm, subsequently impacting gene expression in the zygote.
Epigenetic marks such as methylation may be peripheral to this part of the story.
Some google-whacking came up with this:
Less well studied but equally important epigenetic mechanisms include self-sustaining loops and structural inheritance (Jablonka and Lamb, 2005). Self-sustaining loops refer to the auto-regulation of gene activity via their protein products, while structural inheritance includes the transmission of cell structures from cell to cell (i.e. membranes, mitochondria), or organism to organism (i.e. prions, cilia, egg factors). Together, these mechanisms (and mechanisms yet to be uncovered) contribute to ‘cell memory’ or ‘epigenetic memory’, general terms used to describe the stable inheritance of gene expression patterns from generation to generation. [Note that some biologists consider epigenetics as the stable inheritance of epigenetic marks (Bird, 2007), while others distinguish between epigenetics and epigenetic inheritance (Gluckman et al., 2007; Jablonka and Raz, 2009); see Table 1.] http://jeb.biologists.org/content/213/1/3
I bet Mark Ptashne’s ears were ringing when that was being written.
😉
So trying to grab this football and run with it: differential Maternal Patterning (hmmm… for lack of better words just now) in the Egg Cytoplasm in response to the environment may be part and parcel of auto-regulation of gene activity via their protein products.
This brings us back to your grandfather remark. Mechanisms need not be immediate, ideal or perfect to confer selective advantage.
TomMueller,
Not the soundest of scientific principles! Where one looks for a smoke/fire correlation one often finds it. A meta analysis of all studies, plus unpublished ones, might well find that the correlation does not hold up to the force of large numbers. I remain to be convinced. The lack of a sensible mechanism passing through 2 generations from 4 ancestors, and the likely weakness of selection in this scenario, remain substantial blockers IMO.
Why mess around with human data at all? Can’t they just be mean to mice? I’m not a fan of such experiments, but they are an obvious place to go for hard data.
It’s that panadaptationism thing again!
Yes, Fisher’s sex ratio can have exceptions. I invoked it specifically here in the case of the generality of mammals, the only order in which placenta-competition imprinting can occur, and one where haplodiploidy is absent. The exceptions in Mammalia are caused by stable asymmetry (eg elephant seals). But that is not the rule.
Meiosis is the means by which cryptic ‘haploid organisms’ emerge from their temporary diploid partnerships, irrespective of whether the next step is in- or out-crossing. If inbreeding were adaptive, it would not be through the medium of meiosis, but through the medium of inbreeding.
TomMueller,
The longer the period (the greater the number of generations), the less the power. And let’s not forget the 4-grandparents issue.
Hi Allan
re: The lack of a sensible mechanism passing through 2 generations from 4 ancestors, and the likely weakness of selection in this scenario, remain substantial blockers IMO.
So what’s wrong with
Self-sustaining loops refer to the auto-regulation of gene activity via their protein products,…?
I see methylation co-opted as a mechanism of autogenous gene regulation. The regulation of the IGF2r gene in mice bears an uncanny resemblance to Lambda!
To understand epigenetics, we need first to understand the cytoplasmic transcription factors (and other regulatory elements) that maintain epigenetic memory and how this memory fades as transcription factors and other regulatory elements can dilute. One key candidate mentioned by Ptashne would be miRNAs.
The important point that Ptashne is emphasizing would be that nucleosome modifications are by themselves not self-perpetuating although they may have a lingering effect.
Hmmm… Thinking this over.
Maybe we only need to worry about the one maternal grandmother issue!
TomMueller,
Mainly that I don’t really understand how that is relevant. Something has to pass through 2 generations, and integrate or pick from the epigenetic states of 6 separate ancestral individuals (4 grandparents, 2 parents) to result in one state in the grandchild.
ETA: oops, wrong thread. Meant this to go in the EleP(T|H)ant thread.
TomMueller,
But the Overkalix study is picking up a supposed gender-specific factor through to grand-offspring of the same gender. OK, that’s narrowing things down but they have not (I think) tabled the data differentially between offspring of sons and daughters of the first generation. How, IOW, does a maternally-carried factor affecting granddaughter phenotype get past a male in F1?
Hi Allan
Assuming X-linkage (not clear that is necessary) one of the Grandmother’s Xs ends up in father which he passes to daughter.
I think what may be happening here is that lingering methylation which represents perhaps one toggle setting may not be self perpetuating on its own but is eventually (not immediately erased) along the lines you yourself suggested with your “theoretical islands”.
The methylation state of the grandmother’s X (which will be mosaic/lyonized in her granddaughter) could possibly represent haploinsufficiency and presumably in loss of the transitory epigenetically determined phenotype unless the environment again resets the trigger.
I share your frustration: how indeed it is possible to sort out who is doing what to whom if both grandparents lived together in the same village? The Israeli data should be better. Presumably, some Holocaust survivors (of either gender) met partners who had not experienced starvation.
Just thinking out loud…
I just have to repeat – The regulation of the IGF2r gene in mice bears an uncanny resemblance to Lambda! UNCANNY – I say!
TomMueller,
Over 2 generations it amounts to the same thing for both X and autosome, via either male or female 1st generation – each X has the same chance as each autosome to be in gen2. Still, it seems a bit odd to have a gender-consistent effect in gens0 and 2 while gen 1 doesn’t matter. Keeping parent of origin for 1 gen is (comparatively) easy. But non-genetic gender-related info must survive 2 wipes/resets AND 2 opportunities for reciprocal crossover away from any localised gender label, in the grandparent scenario.
In a way, keeping a state across one ‘organism boundary’ is no more remarkable than keeping it across a mitotic boundary. Because you are, essentially, keeping it across a cellular replication boundary, just cells in different bodies, and duplicated in meiosis I. And you have room in a first-gen diploid for 2 states: both parents are guaranteed a representation. 2 organism boundaries: not so easy … I gen good, 2 gens bad!
Allan Miller,
Hi Allan
– each X has the same chance as each autosome to be in gen2.
Uhmmm … Not exactly
Meiotic recombination between X chromosomes can occur in F1 female but is absent in F1 male
I need to think this through after staring at the data some more.
Hi Allan
You need to check out the latest version of Cell!
http://tinyurl.com/hr3ew97
Remember what Ptashne said regarding Memory (or Lack Thereof).
Genes do not automatically stay “on” or “off” once activated or repressed. Rather, those states of gene expression require the continual activities of the specific regulators to maintain that state of expression. Put another way, continual recruitment of the relevant enzymes is required to maintain the imposed state of gene regulation. Nevertheless, memory effects are important for development, and the question will arise as to how they are achieved.” Mark Ptashne
It turns out that Mark Ptashne was correct (with his unwavering rendition of events comparing the regulation of lambda lysogeny to epigenetics) i.e. the continual recruitment of the relevant proteins (in this case enzymes controlling RNAi) is required to maintain the imposed state of gene regulation that we call epigenetics.
The reason I always liked Ptashne’s version of events was because ancestral responses would be detrimental if the environments of the progeny and the ancestors were different. There needed to be another level of some fine tuning which I already indicated above.
If this report pans out, a lot of textbooks will need to be rewritten and more than a few professors will need to rewrite their lectures. So much for Nucleosome comparisons to RAM! That shibboleth is now slain once and for all!
This is exciting news! Here is the press release:
https://www.sciencedaily.com/releases/2016/03/160328133534.htm