…and this is a 
Epigenetics
Category: Development • Genetics • Science
Posted on: July 22, 2008 1:56 PM, by PZ Myers
Epigenetics is the study of heritable traits that are not dependent on the primary sequence of DNA. That's a short, simple definition, and it's also largely unsatisfactory. For one, the inclusion of the word "heritable" excludes some significant players — the differentiation of neurons requires major epigenetic shaping, but these cells have undergone a terminal division and will never divide again — but at the same time, the heritability of traits that aren't defined by the primary sequence is probably the first thing that comes to mind in any discussion of epigenetics. Another problem is the vague, open-endedness of the definition: it basically includes everything. Gene regulation, physiological adaptation, disease responses…they all fall into the catch-all of epigenetics.
Here's another definition, cited by Mary Jane West-Eberhard in Developmental Plasticity and Evolution. Epigenetic factors are defined as:
…those heritable causal interactions between genes and their products during development that arise externally to a particular cell or group of cellswithin the same individual, and condition the expression of a cell's intrinsic genetic factors (i.e., genome) in an extrinsic manner. In other words, epigenetic factors are the contributions to a cell's environment by genes in other cells of the same individual.
Just to confuse matters even more, I surveyed the long line of developmental biology textbooks on my office shelf, and most don't even mention epigenetics. Not because it isn't important, of course, but because developmental biology basically takes epigenetics entirely for granted — development is epigenetics in action! Compare an epidermal keratinocyte and a pancreatic acinar cell, and you will discover that they have exactly the same genome, and that their profound morphological, physiological, and biochemical differences are entirely the product of epigenetic modification. Development is a hierarchical process, with progressive epigenetic restriction of the fates of cells in a lineage — a dividing population of cells proceeds from totipotency to pluripotency to multipotency to a commitment to a specific cell type by heritable changes in gene expression; those cases where there is modification of the DNA, as in the immune system, are the exception.
In part, the root of the problem here is that we're falling into an artificial dichotomy, that there is the gene as an enumerable, distinct character that can be plucked out and mapped as a fixed sequence of bits in a computer database, and there are all these messy cellular processes that affect what the gene does in the cell, and we try too hard to categorize these as separate. It's a lot like the nature-nurture controversy, where the real problem is that biology doesn't fall into these simple conceptual pigeonholes and we strain too hard to distinguish the indistinguishable. Grok the whole, people! You are the product of genes and cellular and environmental interactions.
With our current state of knowledge, though, we can at least separate the two operationally. We can go into a cell, or into the online databases, and pull out DNA sequences, like this little snippet from human chromosome 15:
gaattctact aatgtttaaa aaattaatac caataaagtc ttacaaaaat atagaagtagWe can also see how mutations that change that sequence affect the organism, and we can also see that sequence being passed on from parent to child. Those are genetic traits; they are characterized by an overall stability, with deviations being the fascinating and important exception.
Epigenetics is messier and more fluid, and therefore harder to pin down. The genome is actually not a simple sequence of letters, it is a more complex chemical structure that is bound up with proteins called histones forming a complex called chromatin. This is what cells are actually working with when they execute a 'genetic program':
Strands of DNA (in blue) are wrapped around spools of histones forming a unit called the nucleosome; these units are folded and wrapped into a great tangled loops and whorls, the chromatin. This is what is modified by epigenetic processes. We can break these processes down into several different categories. The two big ones are methylation of DNA and modification of the histones themselves.
DNA modification. Stretches of DNA can be inactivated by covalently attaching methyl groups, which can interfere with the binding of transcriptional enzymes, and can also be signals to recruit enzymes that modify associated histones. Cells have enzymes called methyltransferases that bind to specific dinucleotides (a cytosine adjacent to a guanine) and attach a methyl group to the cytosine. Methylated DNA is silent DNA.
Histone modification. Those roughly spherical histone complexes also have dangling N-terminal tails that can also be covalently modified by acetylation, phosphorylation, ubiquitination, or methylation. These changes affect how tightly packed the chromatin will be: in loosely packed chromatin, called euchromatin, the DNA is more accessible and more active, while in tightly packed chromatin (heterochromatin), the DNA is more inactive.
Histone variants. All histones are not alike! Some variants are more permissive of transcription, while others facilitate tighter packing. Activity in a region of DNA can be modulated by the kinds of histones used.
Chromosomal arrangement. There is growing evidence that at least some aspects of the 3-dimensional arrangement of DNA in the nucleus is non-random — that is, the DNA isn't a willy-nilly tangle of spaghetti, but folded in some specific ways that bring widely separated regions into association. One of the prettiest examples of this is the control of olfactory receptor expression in mice: by unknown mechanisms, a single specific receptor gene is activated in an olfactory cell by the association of a distant enhancer element with a single receptor gene.
Every other mechanism of gene regulation. Heritable modifications of DNA are easily seen as epigenetic factors, but similarly, just about every known regulatory mechanism is in some sense also heritable. The concentration of transcription factors and RNA in the cytoplasm, for instance, affects levels of gene activity…and those factors are passed on in mitosis as well. Especially by the West-Eberhard definition above, epigenetics opens up into a vast catalog of everything that modifies gene expression.
How about some examples?
One clear example of a long-term epigenetic modification is X chromosome inactivation. Mammalian females have two X chromosomes, while males have only one, which could create problems of differences in dosage — left unregulated, females would have twice the concentration of the gene products found on the X chromosome, and we know that many genetic effects are sensitive to concentration differences. The mammalian strategy is not to make genes on the X in males work twice as hard to compensate, but to instead shut down one whole X chromosome in females. This is accomplished by, largely, extensive methylation of histones on the inactivated X, and by recruitment of repressive histone variants. The chromosome is heterochromatized to shut it down.
Which X chromosome is silenced is heritable. If a cell in a female embryo happens to shut down the X chromosome it inherited from the mother, leaving the paternal X active, all of its subsequent daughter cells will also shut down that same X. This is fixed; all future progeny of that cell, from that early embryonic state until the female grows old and dies, will be using the same single X. This is definitely a long term commitment.
One other interesting phenomenon occurs in eutherian embryos. Initially, the paternal X chromosome (that is, the one carried in the sperm) is always inactivated, and the earliest steps of development are carried out using only the maternal X chromosome. The extraembryonic tissues persist in this pattern, but the embryo itself later briefly activates all X chromosomes, and then in females, randomly shuts down one of them. This leads to the interesting situation that mammalian females tend to be mosaic, with an invisible (except in cases like calico cats) mottling of cells that have arbitrarily shut down one or the other X chromosome. It's this later choice that is locked in for the rest of the individual's life.
Another instance is genomic imprinting. It's not just the X chromosome that is differentially activated or inactivated depending on whether it is maternal or paternal; other genes on non-sex chromosomes also show differences. The best known example is a bank of genes on human chromosome 15. In males, some of these genes are silenced; in females, a different set of genes in the same area are shut down. The pattern of inactivation is perpetuated in the sperm and egg, so sperm cells always carry a chromosome 15 with those genes methylated, while egg cells similarly have the female pattern of inactivation. Now normally, this has no detectable consequences to the embryo. It has one paternal and one maternal copy of chromosome 15, so it still has one copy of each gene that is entirely functional. All is well.
However, there are instances where the embryo must rely on just one of the chromosomes, and then things can go wrong. What if the sperm cell carries a chromosome 15 that has a defective allele, or one that is completely deleted? Then the embryo must use the maternal chromosome 15 copy, but what if that allele is maternally inactivated, or imprinted? Then it effectively has no copies of that gene product to use in development.
Another situation is called uniparental disomy. Sometimes there are errors in mitosis or meiosis called nondisjunction, in which a cell inherits an extra copy of a chromosome (a well known example is Down syndrome, where individuals have an extra copy of chromosome 21, with serious effects). Being trisomic, or having an extra copy, for chromosome 15 is lethal to the embryo, so that no such individuals make it to term. However, sometimes they can be spontaneously rescued by a second mistake, a loss of one of the extra chromosomes, reducing them back down to two copies of chromosome 15. Here's the catch, though: which one is lost is random. If the individual has two copies of the maternal chromosome 15 and one copy of the paternal chromosome 15, and sheds the paternal chromosome, it's no longer trisomic, but it does bear two chromosomes with only the maternal pattern of imprinting. This can also have serious consequences.
Individuals that develop with only maternally imprinted copies of these gene on chromosome 15 have something called Prader-Willi syndrome, a disorder characterized by mental retardation, obesity, and short stature; if instead the individual has only the paternally imprinted copies of chromosome 15, they have Angelman syndrome, a different disorder with severe mental retardation, and characteristic changes in facial features and movement (the original descriptions called them "puppet children" for their howdy-doodyesque appearance and jerky limb movements). These individuals may have identical genetic factors, and the only difference is in the epigenetic modifications of their chromosomes.
Another concern is the role of epigenetics in disease. Some chronic diseases, such as cirrhosis of the liver, are more than just an acute reaction to an environmental insult — they represent long-term changes in the pattern of gene expression in the cell lineages of the organ. Our cells are responsive, and they can be changed epigenetically in our lifetimes.
Some cancers seem to be facilitated by what are called epimutations — changes, not in the DNA itself, but in the pattern of methylation such that genes that play a role in our defenses against cancer are inactivated. Epigenetic silencing of the gene MLH1, for instance, is associated with some colorectal cancers.
One of the ways viruses can affect us is that they insert their genomes into ours — they induce a dramatic genetic change, which can be deleterious and which can be passed on by dividing cells. Epigenetic processes are defenses against the propagation of viral infections. Methyltransferases can sweep through and silence viral insertions, preventing them from promoting viral proliferation.
I began this with a couple of definitions of epigenetics. Perhaps a simpler, non-technical way to think of it all is that it represents a kind of cellular memory that can be passed down to daughter cells. It's not as specific as the sequence of DNA, but it is sufficient to reconstitute the state of gene activity between generations. It's central to understanding development as well as how organisms interact with their environment, and is intertwined and inseparable from our understanding of the gene.
Cavalli G (2006) Chromatin and epigenetics in development: blending cellular memory with cell fate plasticity. Development 133:2089-2094.
Egger G, Liang G, Aparicio A, Jones PA (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature 429:457-463.
Kiefer JC (2007) Epigenetics in development. Dev Dyn 236:1144-1156.
Life Science
Comments
Posted by: Glen Davidson | July 22, 2008 2:04 PM
RNAi also seems to have evolved from defenses against viruses.
Those nasty things appear to have played a huge role in the evolution of life.
Glen D
http://tinyurl.com/2kxyc7
Posted by: PZ Myers | July 22, 2008 2:05 PM
And RNAi ought to also count as an epigenetic process...I tell you, it's epigenetics everywhere.
Posted by: LightningRose | July 22, 2008 2:08 PM
PZ, my apologies for being off topic, but I know you're email is hosed, and perhaps this isn't news to you anyway, but I thought you and other usual suspects might be interested in this 96 tentacled octopus.
http://www.pinktentacle.com/2008/07/monster-octopi-with-scores-of-extra-tentacles/
Posted by: Leukocyte | July 22, 2008 2:10 PM
What is really exciting about epigenetic research is that it might allow an "end around" to bypass the tricky mess that is genetic therapy (see: the "bubble boy" fiasco that pretty much ended gene therapy trials). There would be no need to delete a problematic gene that is driving tumor formation if we could just preferentially silence it. Methinks this is going to get HUGE in the coming years.
On a side note, I would be interested to hear Dawkins' take on this. Has he modified his "selfish gene" hypothesis to take into account these other mechanisms of heritability?
Posted by: LightningRose | July 22, 2008 2:10 PM
oops. I really do know the difference between "your" and "you're". It's my proofreading skills that suck.
Posted by: Leukocyte | July 22, 2008 2:12 PM
@LightningRose - PZ already posted about that creature... scroll back a little from the main page and you'll see it, picture and all.
Posted by: Lago | July 22, 2008 2:18 PM
What ever happened to the simple good ol' days of phenotypic plasticity?
Posted by: Greg Peterson | July 22, 2008 2:19 PM
PBS's NOVA had an interesting basic show on epigenetics called "Ghost in Your Genes":
http://www.pbs.org/wgbh/nova/genes/
Good primer, I thought.
Posted by: Jimbo | July 22, 2008 2:20 PM
Thanks PZ. I will not presume that it was my request for an overview on this topic that resulted in this post, but I did ask for it and here it is! Many thanks.
Posted by: Kim | July 22, 2008 2:20 PM
God? . . . . . . . . . . Ducks and runs..............Posted by: magetoo | July 22, 2008 2:23 PM
Good timing! I've seen the word popping up everywhere lately, but it seems it missed a good explanation of exactly what it means.
...oh well.
Posted by: Muse142 | July 22, 2008 2:25 PM
Spectacular summary of very complicated shiz there.
Of course, this only creates more questions than answers. Clearly the best explanation for all this is that Magic Man Done It.
-P
Posted by: Mike Haubrich, FCD | July 22, 2008 2:30 PM
Or, more properly, "Son, it's epigenetics all the way down."
Seriously, though, with the understanding of epigenetics and development; can we finally get people to stop using a "DNA as computer code" analogy? From what I understand, a single gene can be used to create different traits depending on how/when it is copied and to what use it is put. Doesn't the expression of a gene depend on the neutral network in which it interacts? I was reading and trying to understand an article in PLoS Computational Biology which shows evolution doesn't always find the optimal path towards the development of "fittest" organisms, as long as it makes an organism "fit" for its environment.
I am not sure if I understand the study very well, but here is the author's summary:
So, it seems that DNA doesn't translate codon for protein into a predetermined structure. Or have I missed the point completely?
Posted by: Blake Stacey | July 22, 2008 2:35 PM
Dang it, your science is making me revise my science-fiction novel.
Posted by: Jason Failes | July 22, 2008 2:38 PM
Leukocyte @4: "I would be interested to hear Dawkins' take on this."
From last week's New Scientist:
"What does Dawkins himself think? "The 'transgenerational' effects now being described are mildly interesting, but they cast no doubt whatsoever on the theory of the selfish gene," he says. He suggests, though, that the word "gene" should be replaced with "replicator". This selfish replicator, acting as the unit of selection, does not have to be a gene, but it does have to be replicated accurately, the occasional mutation aside. "Whether [epigenetic marks] will eventually be deemed to qualify as 'selfish replicators' will depend upon whether they are genuinely high-fidelity replicators with the capacity to go on for ever. This is important because otherwise there will be no interesting differences between those that are successful in natural selection and those that are not." If all the effects fade out within the first few generations, they cannot be said to be positively selected, Dawkins points out."
Posted by: miui | July 22, 2008 2:43 PM
I haven't read this yet (this is a spur of the moment reply), but I just wanna thank you for writing a post on Epigenetics PZ!
Yay!
Posted by: Blake Stacey | July 22, 2008 2:46 PM
OK, time for a dumb question.
Epigenetic modifications like DNA methylation and histone jiggery-pokery can affect an organism's behavior, yes? Mouse A and Mouse B have the same genome, but Mouse A had a gene methylated during its embryo phase and grew slightly differently; with its altered body plan, Mouse A interacts differently with other mice. (Maybe it can no longer recognize kin, or something.) Assuming these epigenetic variations are effectively heritable, then selection should act on them.
Question: do we now have to start talking about the selfish epigene?
Posted by: gillt | July 22, 2008 2:47 PM
What I came up with over at bioblog: From a molecular standpoint, epigenetics consists of modifications to DNA, other than mutations, or chromatin which changes gene expression.
And the improved: Epigenetics is the study of modifications of DNA or chromatin that don't change the DNA sequence, yet have an effect on gene expression that is persistent through replication (either cellular or organismic)
Posted by: Jaycubed | July 22, 2008 2:48 PM
It's not surprising that epigenetics is "messy".
Life is messy & unpredictable, as is any emergent property.
From Physics, you might recall the 3body (nbody) problem. It is impossible to absolutely predict the behavior of three (or more) bodies to a single force (ie. gravity) due to their interactions with each other. (In other words, Newton's clockwork god can't accurately tell what time it is.)
Life is far more complicated & messy, with hundreds of factors (ie. "bodies") interacting with each other in complex & various ways (ie. multiple "forces"). The usual focus of science is on component parts (analysis) rather than whole systems (synthesis) where complex properties can easily emerge from simple components. A fine example is found in the behavior of social insects, where a tiny number of preprogrammed behavioral responses can elicit complex social behavior.
Often it is comforting to focus on something relatively simple (ie, DNA) rather than the messiness of functioning living organisms.
Posted by: gillt | July 22, 2008 2:49 PM
What I came up with over at bioblog: From a molecular standpoint, epigenetics consists of modifications to DNA, other than mutations, or chromatin which changes gene expression.
And the improved: Epigenetics is the study of modifications of DNA or chromatin that don't change the DNA sequence, yet have an effect on gene expression that is persistent through replication (either cellular or organismic)
Posted by: Becca | July 22, 2008 2:53 PM
I don't much care for formal definitions of epigenetics... it seems bizare to me that something as pedestrian as a transcription factor regulating levels of gene expression in euchromatin might be included, even though this does not really necessarily mean "reprogramming cell fate"... Yet the ultra-cool recombination that occurs in B-cells and T-cells isn't considered "epigenetic", merely because the developmental reprogramming does occur on the DNA sequence level.
@Mike Haubrich- I am not so sure that particular article is easy to interpert. It sounds more like the evolutionary verison of "when you have a hammer, all your problems look like nails" than DNA sequence != protein function.
Of course, DNA sequence != protein function, but the sequence puts constraints on the chemical composition and therefore spatial constraints that proteins can have. And, since many (coding and noncoding) DNA sequences are also important in regulating temporal and spatial (within the cell) parameters of a protein, they do affect function as well. How much information is in the sequence itself is an interesting question.
Posted by: jj | July 22, 2008 2:55 PM
"can we finally get people to stop using a 'DNA as computer code' analogy? From what I understand, a single gene can be used to create different traits depending on how/when it is copied and to what use it is put"
That's what my genetics professors always say!
Posted by: Akheloios | July 22, 2008 3:02 PM
Are there examples of alleles being shut off or turned on in a foetus by maternal hormonal triggers during pregnancy?
Posted by: Annick Jean | July 22, 2008 3:03 PM
When I taught grade 5, we had a girl with Prader-Willi syndrome. Essentially, we always had to have low-carb snacks on hand for her, otherwise she would start eating anything and everything. Nice to understand what was going on though. Thanks !
Posted by: Zombie | July 22, 2008 3:09 PM
So, I'd heard that the explanation for the incidence of color-blindness in men (more common than in women) was due to the lack of redundancy of genes for building colored light receptors. It seems like X deactivation would also eliminate this redundancy. But obviously it doesn't... what am I missing?
Posted by: Neural Transmissions | July 22, 2008 3:10 PM
Leukocyte #4
What is really exciting about epigenetic research is that it might allow an "end around" to bypass the tricky mess that is genetic therapy
Conversely, epigenetics can very much complicate a straightforward alteration of the genetic sequence.
Nice write up, PZ.
Posted by: Blake Stacey | July 22, 2008 3:14 PM
Um, the way "neutral network" is used in that PLoS Computational Biology article, I believe it refers to the set of nucleotide sequences which are connected by neutral mutations. Each node in the network represents a nucleotide sequence, and nodes are connected to one another if a mutation can turn the first sequence into the second. All the sequences represented by all the nodes in the network are equivalent, in that they map to the same protein (or a functionally equivalent protein). In general, as the authors say, neutral networks
If you start at one node in a neutral network, you can hop around via mutations to lots of of other nucleotide sequences. Going through a non-neutral mutation, a mutation which changes fitness, takes you out of the neutral network. The larger your neutral network, the more possibilities you have for reaching different sequences.
The neutral network is not the same thing as the gene regulatory network, in which the nodes are different genes and the connections tell how the products of one gene affect the expression of another.
Posted by: gillt | July 22, 2008 3:16 PM
However becca, the genesis of the concept of epigenetics was somewhat of a paradigm shift. I think what's cool is simply what you happen to be researching. For me it's hematopoiesis and tumorogenesis in zebrafish.
Posted by: foxfire | July 22, 2008 3:18 PM
PZ, thank you for the well-written article that clearly explains a term that has caused me a lot of confusion. I really enjoy reading your science articles!
Posted by: Brownian, OM | July 22, 2008 3:27 PM
Ahh. Scientific relief from the teeming throngs.
That feels nice.
Posted by: Nerd of Redhead | July 22, 2008 3:32 PM
Wow! PZ, you laid out a complex agrument in a very clear fashion. I learned something. That makes this a good day.
Posted by: Longtime Lurker | July 22, 2008 3:40 PM
Another great science post, the surefire way to leave the godbots behind... your ink squirt, so to speak.
Well played, professor!
Posted by: Helioprogenus | July 22, 2008 3:45 PM
Firstly, Thanks PZ for such a thoughtful post on Epigenetics.
Are there any other mechanisms besides epigenetic that result in identical twins appearing physically different from each other? Often times, they even have opposite handedness, and that's probably also epigenetic in origin. Ultimately, it may be that the question itself is pointless since everything is epigenetic, including the physical appearance of each individual, regardless of being a twin or not.
Posted by: Heleen | July 22, 2008 3:47 PM
I don't see how the definition quoted from West-Eberhard fits in.
Posted by: Mike Haubrich, FCD | July 22, 2008 3:51 PM
Thanks, Becca, Blake and JJ. Sometimes I want a shortcut to understanding this, but it's not so easy for a college dropout with only 9 biology credits.
Posted by: Richard Smith | July 22, 2008 3:54 PM
The diagram of "[t]he two main components of the epigenetic code" really illustrates the truth of the selfish gene. It's all about Me, Me, Me...
Posted by: Ron Sullivan | July 22, 2008 3:57 PM
Oh man, this is so much more fun than the usual pop oversimplifications. Plus: calico cats!
I agree strongly with the profs quoted by jj above. Thinking without Procrustean metaphors like "computers" and "programming" might make things seem more complicated, but it has the advantage of not being misleading. Seems to me that metaphors, like most ideas, are productive only when you have a grip on them and not vice-versa, so you can let go when they ramble off in wrong directions.
Posted by: Blake Stacey | July 22, 2008 4:00 PM
Mike Haubrich, FCD (#35):
I'm glad to do what I can; the knowledge I have is just what I've learned from all the dumb questions I've asked. . . . I'd seen that particular paper mentioned before, so I'd already given it a once-over.
Posted by: Dave UH | July 22, 2008 4:07 PM
Thank you PZ for writing this up. I have been trying to figure this epigenetics stuff out and this was a great guide to pointing me in the right direction.
On a side note, if anyone wants to see what the postmodernist new-age retards have done with epigenetics, just do a quick search on youtube. "Dr. Bruce Lipton
Posted by: bob koepp | July 22, 2008 4:15 PM
Does it help, or only make things yet more confusing, to say that it's developmental capacities, rather than developed traits, that are inherited?
Posted by: C Ridley | July 22, 2008 4:17 PM
Thank you PZ for this fantastic article! I'm soon to begin studying biology at the University of Bath as an undergrad and as such have never heard of epigenetics during my A-level study, until now. It's a really thought provoking topic, hopefully I'll learn more of it at university, thanks for bringing it to my attention now!
Posted by: Odonata | July 22, 2008 4:22 PM
Thanks a lot for the well-written article! I understand epigenetics much better now.
Posted by: Randy Stimpson aka Intelligent Designer | July 22, 2008 4:25 PM
@ PZ
Has the amount of information besides DNA that gets passed from gametes been quantified? If not, what would you estimate it to be on a percentage basis?
Also from my perspective as an engineer, the collection of genes in a genome looks like a massive state machine with genes being turned on and off by various mechanisms. How much of the genome would you estimate is responsible for this regulation?
@ Anyone Else
I will probably take a lot of shit for this question but here it goes:
Perhaps viruses are a mechanisms used by the Designer(s) to propagate non-random modifications to genomes. Has anyone else considered this? If you think this is completely impossible, why?
Posted by: Helioprogenus | July 22, 2008 4:43 PM
@ Randy Stimpson #43, If viruses were the only means of genetic modification, we would still have to explain the origins of viruses within a natural environment. Viruses don't just pop in out of existence. What you're proposing is that there is an intelligent guiding a virus into infecting a host with certain genes that may eventually benefit the host and in turn, effect the evolutionary outcome of said organism. Yet, this is definitely not the case. Besides all the other mechanisms that result in hereditary genetic modification, epigenetic traits as we know them can be passed down, yet we don't know if they're ultimately nullified or not by a certain number of generations.
Posted by: Jason Failes | July 22, 2008 4:44 PM
"Perhaps viruses are a mechanisms used by the Designer(s) to propagate non-random modifications to genomes. Has anyone else considered this? If you think this is completely impossible, why?"
It's not impossible, but if you don't mind, we'll consider all other naturalistic possibilities before concluding that a magic man done it.
I apologize in advance if you are a member of the small group of ID theorists who is actually trying to develop a science. You should realize that the originators of your movement were and are barely-concealed creationists responding to a court ruling and nothing more. If I was you, I would get as far away from them as possible to preserve my own credibility. Try panspermia research.
Another general comment, what makes the idea of a designer so far-fetched, is that in any known case, when a designer designs something, it has an immediate purpose. For example, if we were to terraform Mars, it would be to live there. If we took the alien equivalent of primates and genetically engineered them to be smarter, it would similarly be for some purpose, given human history probably the purpose of enslavement.
If we were intelligently designed:
1) They didn't do a very good job.
2) They either didn't have a purpose or
3) Their society collapsed before that purpose could be realized.
Oh, and in the absence of and actual phenomenon, any speculation about an intelligent designer is so much philosophizing into an old gym sock. Useless.
Posted by: Jason Failes | July 22, 2008 4:47 PM
I meant to say "in the absence of ANY actual phenomenon"
Posted by: Leukocyte | July 22, 2008 4:55 PM
@ Jason (#15) - Thanks! Couldn't have gotten a straighter answer unless he responded himself.
Posted by: Glen Davidson | July 22, 2008 4:56 PM
First, we look for reasons to think it's plausible, rather than following the IDist program of considering everything they've thought up that is not disproven to be "science".
Secondly, no, oddly enough we don't look at parasitic evolving organisms such as viruses and think "designer". It would be strange if viruses were propagating non-random changes when they themselves appear to have enhanced mutations rates in order to supply their own "random mutations" (they're not totally random, but there is no reason to think they're guided) to evolve to survive unpredictable future conditions.
Viruses are doing what the rest of life is doing, evolving without being directed to do so (by all of the evidence we have). They greatly affect evolution, but there is no rationality or intelligence to their existence and persistence.
Glen D
http://tinyurl.com/2kxyc7
Posted by: Owlmirror | July 22, 2008 5:00 PM
Oh, you have no idea....
Hey, perhaps we could, I dunno, study retroviruses and find out what their mechanisms really are?
Sigh. Oh, yes.
http://endogenousretrovirus.blogspot.com/2007/07/ervs-are-functional.html
Also:
http://scienceblogs.com/erv/ervs/
Posted by: Don Cox | July 22, 2008 5:01 PM
Obviously the analogy with computers can be pushed too far - so can any metaphor - but this does sound rather like the behavior of a run-time optimizing compiler, such as is used by Java.
Posted by: Pianismi | July 22, 2008 5:04 PM
I'm so glad to find a combination of a more serious, educating posting AND reasonable, meaningful comments - with content other than "lolz , xtians/atheists suck!" It seems that especially after the whole cracker-episode the blog has become a hostage of meaningless drivel from both sides on the intellectual level of "Your momma so fat..."
Having said this I'm afraid to ask my probably stupid question:
What is the controlling force behind epigenetics then? I understand from your example of liver chirrosis that at least enviromental factors can mess with epigenetic-processes but what constitutes and controls the "normal" balance of methylated parts, histone variants etc.? Seeing as it is called EPIgenetics and not e.g. METAgenetics I'm guessing the answer will be most confusing to a Sunday biologist like me =)
Posted by: Shenda | July 22, 2008 5:31 PM
From #8:
"PBS's NOVA had an interesting basic show on epigenetics called "Ghost in Your Genes":"
I caught the first half of that program and it looked pretty good. The level of complexity that it (epigenetics) adds to development and diversity is overwhelming to me. It *almost* makes me sympathetic to those who throw up their hands and say "God must have done it! It is so much easier that way!!"
Posted by: travc | July 22, 2008 5:41 PM
I sense a bit of a culture clash here, with EvoDevo folks stuck in a bit of a schizophrenic state.
Evolutionary biologists, at least those with a more theoretical bent, rightly focus on non-genetic heritable states. They tend subdivide the broad 'epigenetic' category based upon relative heritability, stability, and plasticity... the factors that matter evolutionary dynamics wise.
Developmental folks do see epigenetics as a kindof 'duh, obviously *rolleyes*' thing. The subdivisions they gravitate to seem mostly mechanistic, which makes perfect sense since discovering those mechanisms is a lot of what developmental bio is about.
I tend to side with the Evo folks. Epigenetics is fundamentally a evolutionary biology term, and defining broad sub-classes (or otherwise narrowing it down) based on the evolutionary dynamics of different heritable mechanisms is a really worthwhile endeavor. Devo should certainly group different mechanisms together as similarities are identified, but this is more of a bottom-up thing.
I don't know if I'm being really clear, but let me put it this way: Since epigentic factors are ubiquitous in developmental biology, the actual term 'epigentic' is pretty useless. Leave it to evolutionary biology where it is actually a useful distinction.
Posted by: Mike Beavington | July 22, 2008 5:44 PM
That is f***ing awesome. Period. I love biology.
Posted by: Ichthyic | July 22, 2008 6:08 PM
I don't know if I'm being really clear, but let me put it this way: Since epigentic factors are ubiquitous in developmental biology, the actual term 'epigentic' is pretty useless. Leave it to evolutionary biology where it is actually a useful distinction.
Clear enough; I thought you highlighted the distinction succinctly.
defining broad sub-classes (or otherwise narrowing it down) based on the evolutionary dynamics of different heritable mechanisms is a really worthwhile endeavor.
I think it would be good to go into a few examples that would actually demonstrate why it's worthwhile.
Have you run across a few good recent cites?
Posted by: Sauceress | July 22, 2008 6:20 PM
#43 Randy Stimpson aka Intelligent Designer
You mean, perhaps those oncoviruses may have been intelligently designed?
http://en.wikipedia.org/wiki/Oncovirus
Posted by: Jared | July 22, 2008 6:30 PM
Damn, PZ, you beat me to it, although you did a better job than I would have... Can you leave Ensatina alone for about 3 more days?
Posted by: LisaJ | July 22, 2008 6:37 PM
Thanks PZ! That was great. I love epigenetics. Freaking cool.
Posted by: Nick Gotts | July 22, 2008 6:57 PM
The first definition given: "the study of heritable traits that are not dependent on the primary sequence of DNA", would include culture, if you judge heritability simply on the correlation between parent and child, without restricting the mechanism. I'm not sure I got the whole of the second, much more complicated definition, but so far as I can see it would allow culture as well. I'm not sure whether this is actually a disadvantage - as both are systems that pass on information acquired by an organism, to its descendants, it would surely be useful to compare culture (at least in non-human animals) with the kinds of epigenetics PZ describes.
Posted by: kemist | July 22, 2008 6:58 PM
One of the coolest things I have seen about epigenetics are the changes to gametes brought on by environmental stresses such as wars or famines. I've seen a study not long ago about how children born of parents which have lived through a famine in their childhood were smaller more prone to diabetes even though they never themselves suffered from malnutrition.
That is what is revolutionary about epigenetics: the possibility of transmitting to offspring an acquired trait brought on by an environmental stress. So-called Lamarckism !
Posted by: Owlmirror | July 22, 2008 7:46 PM
Zombie @#25:
Well, if I understood correctly (and if I didn't, someone will no doubt correct me), you missed the implication of " an invisible [...] mottling of cells that have arbitrarily shut down one or the other X chromosome". That is, some of the retinal cone cells will indeed shut down the X chromosome with the functioning pigment gene, but others will shut down the X chromosome with the defective pigment gene, and will work properly.
As I recall, the development of the retina is to a certain degree random (that is, whether any particular cell becomes a cone sensitive to the red frequencies, the green frequencies, or the blue frequencies, or a rod cell), and the optic nerve takes the gestalt of the signals from these cells anyway.
It's been a while since I skimmed that info, and the visual system is weird and complex, so take that with a grain of NaCl.
Posted by: ERV | July 22, 2008 8:26 PM
One of my research projects is on how loss of epigenetic control of ERVs leads to cancer. Does that answer your question? ;)
Posted by: molliebatmit | July 22, 2008 9:24 PM
To add another example to Zombie's question at #25 and owlmirror's response at #61, females get Duchenne muscular dystrophy at much lower rates than males because the dystrophin gene is on the X chromosome. If you actually look at the muscle cells of a female dystrophin mutation carrier, you'll see that about half of the cells do make the "bad" dystrophin. It's just that your body can deal with a loss of 50% of most proteins with few ill effects.
Pianismi #51:
In many cases, the controlling factors are themselves genetic -- for example, proteins called transcription factors can bind to DNA and recruit histone-modifying proteins to shut down or open up the locus.
My favorite protein is a transcription factor, and it binds to its site in neurons to shut down the transcription of genes that aren't needed in those cells.
Posted by: William Gulvin | July 22, 2008 9:32 PM
An altogether excellent exposition on the subject! And about time. I asked you to do this 2 years ago in a comment on a thread about clonal differences where most everyone seemed to want to ignore (rather understandably, perhaps) epigenetic effects.
And speaking of about time, where DO you find the time and energy, PZ? Remarkable. Maybe you've been working on this for lo these past two years? Please don't tell us that you typed it up in 25 minutes.
Posted by: rhr | July 22, 2008 9:41 PM
Re: DNA as computer code - software can do something rather similar. Ken Thompson (the unix guy) wrote a famous paper back in the 70s called "Reflections on Trusting Trust"
http://cm.bell-labs.com/who/ken/trust.html
He tells a story about how a C compiler comes to know that the sequence '\r' in C source code stands for the ASCII return character, represented by the number 10. If you look at the source code for the C compiler - which is itself written in the C language - you find that it simply defines '\r' as '\r'. The source code must be compiled by a working compiler, and such a compiler will already "know" that '\r' means 10, so the circular definition produces another working compiler that "knows" '\r' is 10, i.e. it's a heritable trait. If a cosmic ray turned the 10 into an 11 (in one particular copy of the binary), and you re-compiled the unmodified source code you would get a compiler that still thinks '\r' is 11, and would pass that onto its "offspring" reliably.
The web browser you're reading this on was compiled with a compiler that inherited this and many other things "epigenetically" (i.e. not encoded in its high-level source code) for many generations, probably beginning with a C compiler written in assembly language sometime in the 80s.
Posted by: pipsqueak | July 22, 2008 9:58 PM
Another Sunday biologist here...
Does this mean that Lamarck gets to come back in from the cold?
Posted by: Jared | July 22, 2008 10:19 PM
to #66
No, epigenetic modifications to DNA are reset during gametogenesis with a few exceptions. Lamarck was still wrong with the "acquired characteristics" thing as he was talking about physical traits such as color, extremity length, etc.. This is more of a "epigenetic modifications can survive for a few generations." This is probably due to RNAi.
Posted by: Mike Haubrich, FCD | July 22, 2008 10:23 PM
Well, thanks, rhr, but how does survivability affect the '\r' being eleven? Computer language, once compiled, still has to be read and interpreted by memory and the memory itself isn't a copying mechanism. It simply does what the intsructions tell it to do. In copying from DNA to tRNA to mRNA the sequences are templates for the structure of protein being assembled and not instructions.
So, while it's intriguing to follow changes in code as if they were mutations I still think that the analogy is misleading.
Posted by: Heraclides | July 22, 2008 10:23 PM
"So, it seems that DNA doesn't translate codon for protein into a predetermined structure. Or have I missed the point completely?"
'fraid so! Sorry... :-)
Here's a very simplified version of the DNA -> codons -> amino acids -> protein structure. Reality is more complex, as evolution tinkers away throwing up quirky variations on the basic scheme, so this is the gist of the thing.
The portion of the DNA encoding a gene is translated to RNA (messenger RNA). Every three adjacent bases of mRNA make up a codon, which provides the binding site for one tRNA. Each tRNA carries a particular amino acid. Each new amino acid is added to those before it, building up a chain of amino in the order given in the gene. Hence, the DNA sequence of the gene specifies the particular order of amino acids in the protein.
The protein fold (or three-dimensional structure) is a consequence of the physical and chemical properties of the particular sequence of amino acids. Here's an explanation I posted on another blog:
Its been known for a long time that some proteins bind near genes to control if they are used or not. So a picture emerges that all that is needed to "drive" a genetic system is the genes and the proteins controlling them. (The other bits being considered subservient to these two.)
What epigenetics does is add other things that can control if a gene is used or not. It doesn't really change the basic process of "reading the gene" (making the mRNA) and converting it into a protein itself, or the process of folding a protein that I outlined above, but adds new ways of controlling the process that starts with a DNA sequence and ends up with proteins. The existing understanding of "how genes are read" hasn't been replaced, so much as added to. [I'm aware of the details for those who want to nitpick: I'm trying to be simple here!]
To rattle on a bit more...
You can chemically modify the DNA in response to environmental events (e.g. methylation and ethylation of DNA bases). These modifications can block proteins from binding that portion of DNA in order to control a nearby gene.
You can modify proteins after they are made, for example adding small carboydrate molecules to specific parts of a protein. (Some people like to write "decorating" proteins!) This includes proteins that hold the DNA in place in the nucleus, wrap it into a compact form (e.g. histones), or those that control if a gene is used (transcription factors), altering their functions. You could add chemical groups to mark the "state" of the gene (active, inactive"), or make the protein inactive or active for a particular function.
Newly identified types of RNA (e.g. RNAi) control parts of the basic process I outlined above.
There is evidence that DNA can be moved within the nucleus, making the DNA available to be "read" (or not). This can be viewed as organising the nucleus into "domains".
DNA can be arranged in loops anchored at the base. Take two "motifs" (specific DNA sequences), bind proteins to them, and pull them together to form a loop. Genes in the DNA within the loop are controlled by protein binding sites with the loop. If you make a loop from two motifs that are further apart, you can include more genes or more binding sites for proteins that control genes, altering how those genes are controlled. [Horribly simplified, again...]
And so on. PZ has given you specific examples of these general things, but I guess putting them another way doesn't hurt!
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