Larry Moran quotes this closing paragraph from an actual, published paper in a respectable journal. I don’t understand what it means. Can somebody explain why these terms are mashed together in this way?
We close this essay by postulating that there has been a pervasive influence of the gene centrism inherent in the Modern Synthesis in conjunction with the Central Dogma of Molecular Biology on biomedical thinking. We believe that this influence has now become counterproductive. Thus, it is critical for new ideas stemming from evolutionary biology highlighted in this special issue of The Journal of Physiology and elsewhere to more fully inform biomedical thinking about the complex relationship between DNA and phenotype. The time has come to stop chasing Mendel.
It’s part of some tirade by physiologists against evolutionary biologists. I have some sympathy for both sides, but this mess just tells me that whoever wrote it knows nothing about evolutionary biology.
Gene centrism seems to be a kind of boogey man here. Isn’t it already a dead issue? Maybe it’s just my developmental biology focus (nah, I don’t know any pure evolutionary biologists who think that way either), but aren’t interactions between environment and genome a major issue nowadays?
They don’t like the “Modern Synthesis”. Maybe they’re confused by the name and think “modern” means current thinking, rather than the thinking of the 1940s, when the synthesis coalesced, and a name was stuck on it to distinguish it from Darwinian thinking. There have been these new developments in molecular biology…
Oh, they don’t like that either. But what’s this about the central dogma? That’s just the idea that information in proteins has no way of being unencoded and directly written back into the genome. Surely they don’t find anything objectionable in that?
I’d like to know what “new ideas” they’re proposing. We already know there’s a complex relationship between genotype and phenotype. I don’t think anyone has been downplaying it.
I lost it at The time has come to stop chasing Mendel
. What does that mean? Is it 1910 again, and people are bickering over Mendelism and saltationism and all that stuff? Mendel sketched a crude and limited skeleton of genetics — no one is limited to Mendel’s models anymore. I teach undergrad genetics, and we spend a couple weeks going over Mendelian basics, because you need to know your ABC’s before you get to do literary criticism, but most of the course is stuff Mendel never imagined. We recently covered epistasis. We just started on imprinting. Epigenetics is coming up soon. I don’t know, do you think Mendel had anything to say about those?
How can anyone know anything about modern evolutionary theory, or genetics, or molecular biology, and seriously argue that we’re chasing Mendel
? And then go on to write papers in which they lecture evolutionary biologists on how they’re doing evolutionary biology wrong?
It’s always a disappointment when scientists keep arguing for/against strawmen, instead of gaining enough knowledge to talk coherently on the subject. Chasing Mendel? I don’t think so Tim….
I now have this incredibly weird image in my head of a bunch of people in lab coats chasing Zombie Mendel… And Mendel proves maddeningly spry for someone dead so long.
As a poet, I know poetry when I see it.
This is a poem.
…yet another reason I know I am not a poet.
Cuttlefish
If you are not a poet, then neither was Robert W. Service.
No, gene centrism is not a dead issue in popularizations, where it seems foundational in such obscure and irrelevant works as The Selfish Gene (which is commonly viewed by the laity as the Modern Synthesis.) Or in the many, many popularizations of something called Evolutionary Psychology. Their inference that the Central Dogma is interpreted as the biochemical proof that genes are everything in popularizations doesn’t seem crazy to me, but it also seems to be their guess as to why people are thinking genes are everything.
As for “time to stop chasing Mendel,” I think it’s pretty obvious they’re trying to come up with a punchy slogan about eschewing simplistic genetics. Actually in popularizations, you don’t actually get much about epistasis, imprinting, epigenetics but an awful lot about the adaptive functions of major blood groups etc.; about sexual selection; about kin selection/inclusive fitness; the genetic basis for behavior traits like cheating detection. My experience in reading internet is that pretending not to even understand something on the grounds it is just too outlandish to have been from a human being, but must be from a Martian is the admission of total, unremitting refusal to countenance an opinion regardless of any evidence or logic.
Your announcement that physiologists are crazy assholes and Evolutionary Psychologists are not is at least honest. Good to know where you stand.
Did I miss something, or did you translate “I have some sympathy for both sides” into ” physiologists are crazy assholes and Evolutionary Psychologists are not”? I probably missed something.
it is indeed.
love those bracket content!
Sort of, yes. But so are the the interactions between libraries and students, and nobody who hears the word library thinks “concrete”, they all think “books”. Get that?
Not a biologist, but what stevenjohnson2 said–
–was where my mind went when I read the quoted bit, and I was a bit surprised you seemed to disagree.
But the paper is presumably talking about professional evolutionary biologists, not laypeople or evo psych yarn spinners. So maybe the authors are off base.
Or maybe they’re just really bad writers.
Agreed that the cited statement is a bit hyperbolic, but that does not mean that the physiologist view is wrong alltogether, that its systems approach of life can not greatly enhance evolutionary theory. What they oppose is not evolution, but adaptationism and gene gentrism, which also form the basis for evo-psych, and which are not dead, seen the success of Pinker and the eternal reprint of The selfish Gene.
The strange thing to me is that both PZ and Larry (if I remember well) at moments rightly attacked adaptationism and evolutionary psychology. PZ’s page carries a quote from Lewontin, and Larry has hailed Gould’s at times.
Could it be that many evolution biologists have too long been hardened in a fight with creationism, and forgot to see allies when they appear?
I am not a scientist, but seen from the populace side, there was too many Pinker, Dawkins and Dennett, and too few Lewontin and Gould. Adaptationist views and gene centric vieww are not outdated, and still at all, seen t
Isn’t imprinting a type of epigenetics?
Just one paragraph leaves out some context. But my best guess is it is saying this: ‘We should not assume that genotype = phenotype”. To which my answer is: Duh. This has been known for about 60 years.
Popular press reporting about evolution or genetics is almost always hyper-adaptationist and often portrays genes as commanding things that rule all, and ignores environmental factors (and ignores things like junk DNA and epigenetics).
But it seems to me most evolutionary scientists don’t make those kinds of mistakes, with the exception of a few fringe areas like evopsych and a few popular writers like Pinker.
I think the physiologist who wrote the paragraph PZ complains about mistook a problem with the popular press for a problem with the science. The problem is real, it’s just not where the physiologist thinks it is.
That’s a weird interpretation of my statement that I sympathize with both sides. What I meant was only that I was trained as a cell biologist/neurophysiologist (JZ Young, Mike Land: awesome), and as an evolutionary developmental biologist. I also teach physiology.
The words “the Central Dogma of Molecular Biology on biomedical thinking” tell me that this was written by some sort of religious pseudo-scientist; most likely a creationist trying to revive that old schtick that science is actually a religion, with a “central dogma” that brave free-thinking out-of-box skeptics like himself are now leading the charge to overthrow.
Writing like this is killing journal articles. Authors are choosing to use inflated nonsensical verbage to convey ideas and sound intelligent instead of clearly and succinctly making a point. The sad thing is peer review let’s it through.
I think I know where Calvin’s letters wound up.
If evolutionary biologists aren’t chasing Mendel (by asserting the supremacy of evolutionarily selected DNA sequence in defining function) why do they insist that much of the biochemical activity detected by ENCODE must be meaningless?
stevenjohnson @ 6
That’s some powerful straw…
siger @ 10
While I tend to agree (and I also was trained as a physiologist in the past), I sincerely would like a more specific example of that “systems approach” to evolution. What does it even mean?
This is not some kind of “us vs them” propaganda war. If we see bullshit from our “allies” we will call it out, we will not cover it to avoid “damaging the public façade of science”.
chris61:
You seriously can’t imagine the situation in which you acknowledge that junk DNA is still junk DNA, while also noting the importance of complex developmental factors and epigenetics and so on? Pathetic gotcha is pathetic.
Because, for the umpteenth time, ENCODE uses a non-totally-specific marker as a PROXY for activity. They don’t prove activity, just that the genes interact with their non-specific PROXY for activity. DUH. It is obvious to everybody not in the ENCODE project this is a huge problem, and has not been adequately addressed.
Good news! We can stop chasing Mendel, Mendel has been caught.
And it only took me 20 seconds with a search engine to find him.
Re: #16, Dylan
Right? I’m not an academic, but I read a lot of journals because the writing is usually succinct and clear and logical–everything I want to achieve as a writer. But yeah, in recent years there’s been a downturn in quality. PZ’s title is perfect, sciencey word salad, indeed.
@20 anteprepro
But how is junk DNA identified? It’s identified based on its sequence. My comment was not intended as a gotcha but to point out why those interested in medical science might feel that evolutionary biology was placing undue emphasis on DNA sequence and not enough on other measures of function.
@ 21 Nerd
Yes, Nerd they use biochemical activity as a PROXY for function. Just as evolutionary biology uses sequence as a PROXY for function. Which PROXY for function is more useful depends on what you’re looking at (and for).
Yeah, no shit. This was hammered into my head on the first day of undergrad Bio III “Evolutonary Genetics” lecture. That was 10 years ago (I think), and from what I gathered, it wasn’t in any way revolutionary at the time.
It’s a more emotive way of saying “Use our ideas!” because just presenting the data is not rhetoric. Maybe science is not so competitive now that such language is thought to be helpful.
My first attempt at compacting that paragraph down yielded,
“Biomedicine is being wrongly biased by the modern synthesis and the central dogma. We think our new bias will be rational instead of irrational.”
Chris61:
Not quite true. Evolutionary biology uses sequence conservation as a proxy for function, while ENCODE used some things that randomly generated sequences commonly do as a proxy for function. There’s an obvious reason why functional sequences should generally be conserved over evolutionary time, but I can’t think of a reason why a method that detects randomly generated sequences should also detect function. Can you? And what exactly would you be looking for in the latter case?
Can there be one single thread about evolution in which chris61 doesn’t make it about their hobby horse?
Word salad is delicious in a post-modern fusion cuisine magazine … oh wait; Journal of Physiology.
I’ll go out on a limb here and speculate that somebody isn’t getting the grants that the ‘Mendel-chasers’ are getting.
‘counterproductive influence on biomedical
thinkingfunding.’When in doubt – follow the money.
Raging Bee @15:
The phrase: “Central Dogma of molecular biology” is not a reference to a religious dogma, but was introduced in the mid-20th century to describe the notion of information flow from chromosomal DNA to messenger RNA and then via ribosomes and transfer RNA to protein primary sequence structure — and most importantly (as PZ indicates), not the reverse. When I was learning about it in grad school in the ’60’s, I always figured that the phrase was meant to be cautionary, to warn that while it described much of what was being discovered about the biochemistry of genes, it was likely not the whole story.
At the same time, we were also being taught about Mendel, and Bovari and Sutton’s theory that the dance of chromosomes seen under the microscope in meiosis was the physical basis for the rules of Mendelian inheritance. And how Mendel appeared to have been very lucky (or perhaps he edited his observations?) to have never had his simple story of inheritance in garden peas messed up by gene linkage. Again, the more complete story was, and is, more complicated. Don’t let the “dogma’s” blind you to that.
Perhaps that is what the authors of the quoted passage are trying to get at when they write about “chasing Mendel” — dig deeper, don’t be satisfied with the initial simplistic explanations. But after reading Larry Moran’s post at Sandwalk, I’m not so sure. What Larry seems to be decrying is that these physiologists appear to want an alternate Dogma, in which biology is purged of that pesky notion of random mutation, in favor of processes in which the physiology and phenotype of the organism (especially the human organism) actively builds the complement of genes to carry it’s mission to the next generation. Triumph of the will, indeed.
A deep fear of randomness is so widespread that it is surprising that it has no name. Religion provides a ready solace in most instances. It is only when scientists tie themselves in knots trying to deny its existence while retaining a natural interpretation of reality (seen in both physics and biology), that the primal fear becomes clearly evident. Perhaps that’s at work here; Larry seems to suspect something like that. Anyone want to review the entire special issue for us to help clarify the matter?
Coming at this with no domain knowledge or opinion on the claim, I still hate it.
The bloated writing is a tipoff that the author wants to sound like they’re saying something very important and original, which is itself probably a tipoff that they haven’t thought it through (since it is rare to have both in the same paper).
Translation: We believe biomedical thinking has been harmed by the influence of gene centrism in the Modern Synthesis along with the Central Dogma of Molecular Biology.
Note: We already figured out that you’re closing the essay (the page bottom is in our peripheral vision). We can assume the influence is pervasive or you wouldn’t be making such a big stink about it, so we can strike that. You don’t need to keep anyone in suspense about whether you think the influence is good or bad, so why not state this up front?
Peer review isn’t just to address scientific accuracy. It would be totally reasonable to ask for a rewrite in this case. In my experience (different field and some time back) the referee will usually complain about any conclusion that drifts beyond a very narrow interpretation of the results.
@27 John Harshman
When a geneticist looks at a DNA sequence they see a string of letters on a page. When a protein interacts with DNA it interacts with a structure made up not only of DNA but other cellular components. So sure, I can think of reasons why the functionality of a DNA fragment might be conserved even though its primary sequence wasn’t. But apart from that, functionality as used by evolutionary biology doesn’t even begin to address what that function might be and what that function might be is an important question.
zenlike: So, what exactly is chris61’s hobby horse?
chris61: Sure, function can be conserved even when sequence isn’t, but sequence conservation is the way to bet. We miss a few functional sequences (and a few more in which positive selection actively changes the sequence), but we also don’t get vast numbers of false positives. Addressing what the function actually is would be the next step, but I don’t see ENCODE as having taken that step. Do you?
@33 John Harshman
Sequence conservation is the way to bet when looking at coding sequences because we know how DNA/RNA sequence is read to make protein. We can account for genetic code redundancy and we can pretty confidently predict that insertions or deletions that aren’t multiples of three will disrupt the protein. We don’t know how DNA/RNA sequence is read to make a promoter or an enhancer. Genetic code redundancy is irrelevant and we can’t predict based on sequence alone how insertions or deletions will affect function.
Yes, I do. ENCODE’s annotation shows certain biochemical markers (such as binding of RNA polymerase and certain histone post translational modifications) associated with promoters, other combinations with enhancers and others with repressed genes. How well that annotation will hold up for specific sequences remains to experimentally tested but the literature suggests that the annotation is proving useful in identifying promoters and enhancers at least.
Actually, we have some ideas on consensus sequences for lots of promoters. And those sequences are somewhat conserved, though not to the degree that protein-coding sequences are. There are also a number of conserved sequences that produce untranslated RNAs or are regulatory sequences of various sorts. Conservation is a pretty good guide to function throughout the genome, not just exons.
On the other hand, it seems very unlikely that the great bulk of ENCODE’s “markers” show anything other than spurious binding unassociated with any real function, as would (I repeat) be expected in any collection of random DNA sequences. I’m sure some of those sites have real functions, but most of that data must be garbage.
It means you don’t have to eat your peas and you still get cake.
Back when I was teaching, my favourite phrase was “Phenotype is genotype as seen through the lenses of development and environment.” Nature vs. nurture is a false dichotomy; we are no more pre-programmed robots than we are tabula rasa.
John Harshman
ENCODE, if that wasn’t really clear.
No fuckwit, they us a PROXY test and claim biological function, they don’t prove function with that test. You misstated my position, and those of REAL scientists who disagree with you. Typical of your dishonesty, and that of the project.
Example, we have a solution product at work that requires us to make to a given assay of 60%. Since production doesn’t have the equipment and training to run that assay, and the test requires hours for a value, they can use a couple of proxy tests, like density or refractive index, to determine if they are close enough with those parameters that the solution will pass final product testing. Those test do measure assay, and to pretend they do is wrong. Assay, like true function, requires a separate test.
Correction for the next to last sentence in #39
@ 39 Nerd
Okay. So how do REAL scientists determine whether or not DNA is functional and why is their assay better than ENCODE’s?
41: We use a number of assays to determine the specific function of a given bit of DNA. One of the simplest is to look for RNAs that have sequence similar to that of the DNA in question. Of course, we have to be careful because many bits of DNA in the genome look a great deal like functional genes, but for a variety of reasons, they don’t actually encode a product any more. We call these bits of DNA pseudogenes, and they’re everywhere in the genome. Real genes (with a few exceptions, mostly histone genes) have introns, which are bits of DNA stuck in between the coding parts of a gene (the exons) that must be spliced out of the RNA made from the gene to make a functional mRNA. Introns frequently have important roles in the regulation of gene expression, as they may contain promoter seuqences or they may code for micro RNAs that regulate the stability of mRNA. We can tell if these bits have biological function using RNA binding assays like CLIP. Therefore, if we want to know if a gene is real or not, we can look for introns and other things like inappripriate stop codons that tell us of a gene is functional or not. Of course, we can always look for the protein that a gene-like region of the genome should encode. To find promoter regions, we use assays like linker scanning mutagenesis, reporter assays, etc. I’ll let you look those up. Might be good for you. The point is that the methodologies used by Encode ignore the complexity of biological function in favour of a simplistic and wrongheaded assumption that binding means function.
The above was written by a virologist, so apologies to any molecular biologists who happen upon it. It may well not be entirely correct.
@42 A.R.
You seem to be implying that RNA-protein binding implies function but DNA-protein binding (as measured by ENCODE) doesn’t.
44: Yep. Pretty much (though there are caveats, and RNA binding is still not absolute evidence of function). The difference requires an understanding of the roles of DNA and RNA in the cell. In everything but viruses, DNA is largely storage. On the other hand, RNA serves in a transient effector role. That means that with the exception of certain introns, there isn’t that much junk RNA sitting about, and you wouldn’t expect there to be, given its role.
@45 A.R.
What is your evidence/argument that DNA is largely storage?
How about seventy years of molecular biology? The fact that no common effector functions have been described for DNA (NETs being an interesting exception)? How about the fact that the vast majority of the known biological processes involving DNA are directly or indirectly related to its storage function? Your hyperskeptic bullshit will not work here.
Uh, Raging Bee, “central dogma” is a self-ironic name chosen by a molecular biologist for “DNA makes RNA makes protein”. Your conclusion is wholly unwarranted.
RNA replication has been discovered, and so has reverse transcription (“RNA makes DNA”), although they’re both much less common than transcription and DNA replication. Reverse translation, however, has never been found; the central dogma remains a useful rule of thumb.
ENCODE discovered one kind of biochemical activity: whether proteins bind to the sequences in question.
If you’d know any pretty basic chemistry or indeed physics, you’d know that such binding is a stochastic affair. Everything sticks to everything at a nonzero probability. ENCODE rests on the assumption that proteins binding to DNA is an all-or-nothing affair, and that assumption is painfully wrong.
Mendel or inheritance in general are orthogonal to this.
First of all, why wouldn’t it be? There is no enzyme that recognizes useless DNA and cuts it out, and it’s very hard to imagine how any such thing could evolve.
@47 A.R.
Protein binding to DNA regulates cellular RNA synthesis. Protein binding to RNA regulates RNA stability and translation. I still don’t see why you consider the latter activity as largely functional and the former as largely non-functional.
Lack of specificity. Which gives FALSE POSITIVES. DUH. Everybody but ENCODE appears to know that.
Because, like Nerd said, there are too many false positives with DNA. Too much extra shit that proteins can bind to without actually doing much of anything. Nonfunctional genes, for example, may have partly functional promoter regions that bind to elements of the polymerase complex, but is that actual biological function, or is is random noise? I say the latter.
@48 David
If by useless, you mean DNA that could be deleted without affecting phenotype, then I would agree that some fraction of the human (or that of any species) must certainly be useless. Some fraction of the transcriptome could no doubt also be lost without affecting phenotype. Some protein coding genes can be deleted without affecting phenotype. ENCODE doesn’t address any of that because that’s not how ENCODE defined function. If you want to define functional DNA as DNA that is indispensable, it is not a particularly useful definition in the sense that there is no practical way to test that for any specific DNA sequence under all possible conditions.
ENCODE defines function as “is transcribed at all ever” without considering the possibility that sometimes things are transcribed by mistake. That’s not a standard of functionality that any sensible biologist would accept.
@51 A.R.
Okay. So you are dismissing some fraction of the ~8-10% of biochemical activity that ENCODE ascribes to protein binding as being random noise. I don’t agree but even so, that leaves the 60-80% of biochemical activity that ENCODE ascribes to transcription. You also said above that there isn’t a lot of junk RNA. On what grounds do you dismiss RNA as random noise?
Most of those (typically rare) transcripts are degraded quickly after being transcribed for any number of regions, ranging from nonsense-mediated decay to lacking polyadenylation sequences. The point is that those RNAs are quickly degraded and almost certainly have no effector function. Recall that 80% of cellular RNA is rRNA, about ~15% is tRNA, ~3% is mRNA, and the remaining ~2% are small RNAs like microRNAs etc. The cell is very good at getting rid of non-useful RNA, and the nature of RNA is in and of itself unstable.
^above should read “after being transcribed for any number of reasons”. I thank autocorrect for that error.
Except when it doesn’t.
There isn’t a lot of junk RNA at any single point in time – but there’s a lot of junk transcription…
@55 A.R.
mRNAs, especially those encoding regulatory proteins, may also be short lived and a lack of polyadenylation sequence is clearly not diagnostic for lack of function (i.e. histone mRNAs). So again, how do you decide that RNAs that are short lived have no effector function or for that matter, decide (without testing) that the function might not lie in the act of transcription itself (which clearly affects chromatin state) rather than in the product?
@57 David
Very true. Not all protein binding will regulate gene expression. But my question was why RNA protein binding should be considered inherently more likely to be functional than DNA protein binding.?
If a transcribed RNA is to have any effector function at all, it must be translated or processed into effector RNAs like micro RNAs and ribozymes. Very short lived RNAs are only useful for the former, and not very useful at that in reality. As for transcription , sure, it does, but you do realize that quite a bit of junk DNA is well isolated from coding regions, and as such chromatin structure modification there would not have a particularly appreciable effect on any coding regions. Furthermore, what function do you assign to all of the Alu sequence in the human genome?
You still don’t get the difference in role between DNA and RNA, do you? Functional RNAs by their very nature do not contain much junk sequence (an mRNA is essentially just cap-UTR-CDS-UTR-tail). DNA, on the other hand does have the capability for harbouring large stretches of junk sequence that might bind proteins without any biological significance.
@60 A.R.
This statement seems to imply that functional RNAs encode proteins and that only functional RNAs will bind proteins. There are plenty examples of RNAs that don’t encode protein but nonetheless have clearly demonstrated functions that are crucial to the cell. In at least some cases, that function requires protein binding to the RNA. Xist, the non coding RNA that is required for X chromosome inactivation comes to mind.
You must have been ignoring my references to micro RNAs, ribosomal RNAs, and tRNAs, because I’ve made it perfectly clear that RNA does not need to be translated to have effector function. My reference to mRNA structure was made as an example of the lack of “junk” in effector RNA. I’m not certain as to what you are getting at by mentioning XIST, other than to say that noncoding RNAs have functions, which I have already stated several times. Please remember that you’re talking to a scientist with multiple advanced degrees, not a layperson.
@62 A.R.
We agree that non-coding RNAs have functions and we agree, I assume, that some short lived RNAs have functions. You say there is very little junk RNA so I’m still trying to determine how you define junk RNA and how you distinguish junk RNA from non-junk RNA. Do you, for example, consider the RNA that is removed by splicing to be ‘junk’ RNA? If so how would you classify RNA that is removed in some alternatively spliced isoforms and not in others?
@62 A.R.
Sorry, hit the post comment button too soon. The question is not just how you distinguish junk RNA from non-junk RNA but how you do it to such a degree of confidence that you can say that most transcription is random noise?
Actually, a surprising proportion of transcription is not random noise. Transcriptional regulation is quite tight, and even if an RNAP manages to bind and initiate transcription, the transcription event may be prematurely halted for a variety of reasons (likely the fate of most of ENCODE’s “transcripts”). As for the rest of your argument, alternatively spliced introns at the DNA level are quite functional, and nobody is saying they aren’t. Even introns that are always spliced out may have some function in regulation of transcription or they may encode micro RNAs. Junk RNA (as opposed to garbage RNA), the product of junk transcription (essentially all of what ENCODE is hailing as “functional”) is very, very transient, which is part of the reason it doesn’t persist for long, and why it is not well represented in various measures of total cellular RNA. Junk RNA has no effector function, and is rapidly recycled. But this, ultimately is all beside the point, because so much of the sequence that ENCODE is calling functional consists of pseudogenes, Alu sequence, transposons, etc. that are not particularly well conserved. Only about 10% of the genome is subject to purifying selection according to relatively recent work, which would mean that 70% of ENCODE’s “80%” is being maintained without selection, or is somehow invulnerable to mutation. Both are ridiculous notions that fly in the face of modern evolutionary theory, and could only be held by persons with the intellectual capacity of a Discovery Institute “researcher”. You should really read this article.
@ 65
Read it thanks. It says a lot of things that are at odds with the literature. For example:
they argue that functional regions of the genome should evolve more slowly than non functional regions. In fact protein coding regions evolve more slowly than non coding regions while promoters appear to evolve somewhat more quickly and enhancers more quickly yet. All are functional and in fact it’s an observation that isn’t really very surprising since it is pretty widely accepted nowadays that chances in the timing and location of gene expression rather than changes in the genes expressed are what distinguishes one species from another among closely related multi cellular organisms. Graur et al also note that ENCODE used almost exclusively pluripotent stem cells and cancer cells which are known as transcriptionally permissive environments. I see this as a feature not a bug given that stem cells and cancer cells are medically very relevant. Graur et al specifically describe three classes of sequences “that are known to be abundantly transcribed, but are typically devoid of function:pseudogenes, introns and mobile elements”. You and I (and the literature) have agreed that introns are in fact functional. Graur cites a paper describing the knock out of introns from yeast genes failing to have an effect on growth as indicative of a lack of function of the majority of introns. One can in fact knock out many coding sequences in yeast genes and still fail to show an effect on growth. Growth in a petrie dish is not a very sensitive assay for function. With regard to his second class of sequences devoid of function, there are multiple examples in the literature of mobile elements that are responsible for human disease. Not a lot of examples to be sure but that is likely at least in part because until the advent of whole genome sequencing, nobody was looking for them. Elements causing human disease may not be considered functional from an evolutionary POV but they certainly are from a medical one. There is also a lot of literature suggesting that Graur’s third example, pseudogenes, can also be functional.
Firstly, promoter regions are conserved to an extraordinary degree. There is very, very little deviation in terms of identify between two individuals of a given species, and precious little difference in terms of similarity between closely related species. Enhancers are a bit of a different story, but the selective pressure on these regions is still orders of magnitude higher than that on any region ENCODE is attempting to define as functional. In fact, those regions include the VNTRs that forensic molecular biology uses to identify individuals. As for this:
No. Not really. At least not to the extent that you are trying to claim. Hard-coded genetic diversity crucial to species diversity, at least as much as the process of development. I say again: Phenotype is genotype seen through the lenses of development and environment. And how, by the way, do you think those changes in gene expression are achieved? By the products of other genes, of course!
Moving on to the rest of it, I’m afraid you’ve lost the plot a bit. Medical relevance is not what is important here. The question is “in a normal human, how much of the genome has relevant biological function”. How, exactly, do cancer cells, HeLa cells in particular, represent normal human cells? They don’t. In fact, I recently recommended a paper I reviewed for rejection based upon its extensive use as HeLa as a model system for viral function in vivo.
Not every intron is functional. Some are, in fact, just junk.
Indeed, it is not. However, it is a very specific assay for function. ENCODE has chosen to go the other way, throwing specificity out the window entirely in favour of sensitivity. This leads to an unacceptably high rate of false-positives.
Again, you’ve lost the plot. Relevance to disease is not relevance to normal function. ENCODE is not making claims about medical relevance, they are making claims for normal function, using the wrong definition in the wrong way inconsistently, from data gathered using the wrong models in the wrong cells. That, I believe makes ENCODE meta-wrong.
As for pseudogenes, the only hard evidence that I am aware of is that they contribute to qPCR headaches. Now, a few here and there might just be important in some odd way, but even if we add them together with the 10% that is generally accepted, and some other stuff that might have real, relevant function, we’re still looking at about 12-15% of the genome having relevant biological function. The last time I checked, 12-15% did not equal 80%.
Of course. But sequence, conserved or otherwise, doesn’t tell you anything about the changes in gene expression that occur during development or in response to environment. The biochemical activities ENCODE is measuring do.
Of course medical relevance is important. Why else bother to ask how things work in normal humans if not to understand how things go wrong in disease?
Nope. ENCODE is looking at a picture that is far too reductionist using the wrong cells to gather any reasonable data in that direction. And sequence can actually tell you a great deal about how development will progress, if you know what to look for.
No, it isn’t. ENCODE’s stated goals relate to normal function. You have to understand how something works normally before you can have any hope of understanding pathology. There is a reason we don’t use HeLa cells for much any more, they are not representative of real human cells. And neither is any of ENCODE’s data. Frankly, I want to see retractions of a few of their papers.
By the way, you sound a great deal like an undergrad. I should know, having taught undergrads for a few years. Advice for the future: “sexy” science is not always good science, and everything published in Science or Nature is good science, and ENCODE is a great example of that.
^Should read *is not good science
Really? I’ll have to take your word for it as I haven’t taught undergrads for many years.
Agree with the first two parts of that sentence and disagree with the third obviously.