We learned a lot about genes and gene expression in the second half of the 20th century. We learned that genes are transcribed and we have a pretty good understanding of how transcription initiation complexes are formed and how transcription works.
We learned how transcription is regulated through promoter strength, activators, and repressors. Activators and repressors bind to DNA and those binding sites can lie at some distance from the promoter leading to formation of loops of DNA that bring the regulatory proteins into contact with the transcription complex. Much of our basic understanding of this process was derived from detailed studies of bacteriophage and bacterial genes.
THEME:
Transcription
Later on we learned that eukaryotic genes expression was very similar and regulation also required repressors and activators. We discovered that gene expression was associated with chromatin remodeling that opened up regions of the chromosome that were tightly bound to histones in 30nm or higher order structures.
Building on studies in prokaryotes, we learned about temporal gene regulation and differentiation. Much of the work was done in model organisms like Drosophila, yeast, C. elegans, and various mammalian cells in culture.
By the end of the century I was pretty confident that what I wrote in my textbook was a fair representation of the fundamental concepts in gene expression and regulation.
Turns out I was wrong as I just discovered this morning when I read the opening paragraph of a review by Rivera and Ren (2013). Here's what they say ...
More than a decade has passed since the human genome was completely sequenced, but how genomic information directs spatial- and temporal-specific gene expression programs remains to be elucidated (Lander, 2011). The answer to this question is not only essential for understanding the mechanisms of human development, but also key to studying the phenotypic variations among human populations and the etiology of many human diseases. However, a major challenge remains: each of the more than 200 different cell types in the human body contains an identical copy of the genome but expresses a distinct set of genes. How does a genome guide a limited set of genes to be expressed at different levels in distinct cell types?
Wow! The textbooks need to be rewritten! We didn't learn anything in the last century!
It took me the whole first paragraph of this paper to realize that the rest of it was probably going to be worthless unless you were interested in technical details about the field. That's because I'm not as smart as Dan Graur. He only read the title, "Mapping Human Epigenomes" and the abstract before concluding that the authors were speaking in newspeak1 [A “Leading Edge Review” Reminds Me of Orwell (and #ENCODE)].
The Rivera and Ren paper is a "Leading Edge" review in the prestigious journal Cell. It covers all the techniques used to study methylation, histone modification and binding, transcription factor binding, and nucleosome positioning at the genome level. According to the authors, people like me were fooled by studies on individual genes, purified factors, and in vitro binding assays. That didn't really tell us what was going on.
Apparently, the most effective way of learning about the regulation of gene expression in humans is to analyze the entire genome all at once and read off the data from microarrays and computer monitors. (After shoving it through a bunch of code.)
Overwhelming evidence now indicates that the epigenome serves to instruct the unique gene expression program in each cell type together with its genome. The word "epigenetics," coined half a century ago by combining "epigenesis" and "genetics," describes the mechanisms of cell fate commitment and lineage specification during animal development (Holliday, 1990; Waddington, 1959). Today, the "epigenome" is generally used to describe the global, comprehensive view of sequence-independent processes that modulate gene expression patterns in a cell and has been liberally applied in reference to the collection of DNA methylation state and covalent modification of histone proteins along the genome (Bernstein et al., 2007; Bonasio et al., 2010). The epigenome can differ from cell type to cell type, and in each cell it regulates gene expression in a number of ways—by organizing the nuclear architecture of the chromosomes, restricting or facilitating transcription factor access to DNA, and preserving a memory of past transcriptional activities. Thus, the epigenome represents a second dimension of the genomic sequence and is pivotal for maintaining cell-typespecific gene expression patterns.
Not long ago, there were many points of trepidation about the value and utility of mapping epigenomes in human cells (Madhani et al., 2008). At the time, it was suggested that histone modifications simply reflect activities of transcription factors (TFs), so cataloging their patterns would offer little new information. However, some investigators believed in the value of epigenome maps and advocated for concerted efforts to produce such resources (Feinberg, 2007; Henikoff et al., 2008; Jones and Martienssen, 2005). The last five years have shown that epigenome maps can greatly facilitate the identification of potential functional sequences and thereby annotation of the human genome. Now, we appreciate the utility of epigenomic maps in the delineation of thousands of lincRNA genes and hundreds of thousands of cis-regulatory elements (ENCODE Project Consortium et al., 2012; Ernst et al., 2011; Guttman et al., 2009; Heintzman et al., 2009; Xie et al., 2013b; Zhu et al., 2013), all of which were obtained without prior knowledge of cell-type-specific master transcriptional regulators. Interestingly, bioinformatic analysis of tissue-specific cis-regulatory elements has actually uncovered novel TFs regulating specific cellular states.
So, what are all these new discoveries that now elucidate what was previously unknown; namely, "how genomic information directs spatial- and temporal-specific gene expression programs"?
This is a very long review full of technical details so let's skip right to the conclusions.
Six decades ago, Watson and Crick put forward a model of DNA double helix structure to elucidate how genetic information is faithfully copied and propagated during cell division (Watson and Crick, 1953). Several years later, Crick famously proposed the "central dogma" to describe how information in the DNA sequence is relayed to other biomolecules such as RNA and proteins to sustain a cell’s biological activities (Crick, 1970). Now, with the human genome completely mapped, we face the daunting
task to decipher the information contained in this genetic blueprint. Twelve years ago, when the human genome was first sequenced, only 1.5% of the genome could be annotated as protein coding, whereas the rest of the genome was thought to be mostly "junk" (Lander et al., 2001; Venter et al., 2001). Now, with the help of many epigenome maps, nearly half of the genome is predicted to carry specific biochemical activities and potential regulatory functions (ENCODE Project Consortium, et al., 2012). It is conceivable that in the near future the human genome will be completely annotated, with the catalog of transcription units and their transcriptional regulatory sequences fully mapped.
I hope they hurry up. Not only do I have to re-write my description of the Central Dogma2 but I'm going to have to re-write everything I thought I knew about regulation of gene expression and the organization of information in the human genome. That's going to take time so I hope the epigeneticists will publish lots more whole genome studies in the near future so I can understand the new model of gene expression.
Keep in mind that this paper was published in Cell where it was rigorously reviewed by the leading experts in the field. It must be right.
[Image Credit: Moran, L.A., Horton, H.R., Scrimgeour, K.G., and Perry, M.D. (2012) Principles of Biochemistry 5th ed., Pearson Education Inc. page 647 [Pearson: Principles of Biochemistry 5/E] © 2012 Pearson Education Inc.]
1. Newspeak was first described in 1984 proving, once again, that George Orwell (Eric Arthur Blair) was a really smart and prescient guy. For another example see: What Is "Science" According to George Orwell?.
2. Apparently I didn't read the Crick (1970) paper as carefully as they did.
Rivera, C.M. and Ren, B. (2013) Mapping Human Epigenomes. Cell 155:39-55 [doi: 10.1016/j.cell.2013.09.011]
I'm interested in how scientists read the scientific literature and in how they distinguish good science from bad science. I know that when I read a paper I usually make a pretty quick judgement based on my knowledge of the field and my model of how things work. In other words, I look at the conclusions first to see whether they conflict with or agree with my model.
Many of my colleagues do it differently. They focus on the actual experiments and reach a conclusion based on how the perceive the data. If the experiments look good and the data seems reliable then they tentatively accept the conclusions even if they conflict with the model they have in their mind. They are much more likely to revamp their model than I am.
I'm about to give you the conclusions from a recently published paper in Nature. I'd like to hear from all graduate students, postdocs, and scientists on how you react to those conclusions. Do you think the conclusions are reasonable (as long as the experiments are valid) or do you think that the conclusions are unreasonable, indicating that there has to be something wrong somewhere?
The paper is Venters and Pugh (2013). It's title is Genomic organization of human transcription complexes. You don't need to read the paper unless you want to get into a more detailed debate. All I want to hear about is your initial reaction to their final two paragraphs.
Consolidated genomic view of initiation
...The discovery that transcription of the human genome is vastly more pervasive than what produces coding mRNA raises the question as to whether Pol II initiates transcription promiscuously through random collisions with chromatin as biological noise or whether it arises specifically from canonical Pol II initiation complexes in a regulated manner. Our discovery of ~150,000 non-coding promoter initiation complexes in human K562 cells and more in other cell lines suggests that pervasive non-coding transcription is promoter-specific, regulated, and not much different from coding transcription, except that it remains nuclear and non-polyadenylated. An important next question is the extent to which transcription factors regulate production of ncRNA.
We detected promoter transcription initiation complexes at 25% of all ~24,000 human coding genes, and found that there were 18-fold more non-coding complexes than coding. We therefore estimate that the human genome potentially contains as many as 500,000 promoter initiation complexes, corresponding to an average of about one every 3 kilobases (kb) in the non-repetitive portion of the human genome. This number may vary more or less depending on what constitutes a meaningful transcription initiation event. The finding that these initiation complexes are largely limited to locations having well-defined core promoters and measured TSSs indicates that they are functional and specific, but it remains to be determined to what end. Their massive numbers would seem to provide an origin for the so-called dark matter RNA of the genome, and could house a substantial portion of the missing heritability.
Looking forward to hearing from you.
Keep in mind that this is a Nature paper that has been rigorously reviewed by leading experts in the field. Does that influence your opinion?
Venters, B.J. and Pugh, B.F. (2013) Genomic organization of human transcription initiation complexes. Nature Published online 18 September 2013 [doi: 10.1038/nature12535] [PubMed] [Nature]
Stephen Meyer is trying to make the case that the primitive animals of the Cambrian explosion really did arise suddenly as fully formed and distinct species. He says that the evidence points to God(s).
Scientists, on the other hand, have been exploring other possibilities and testing various models. They have shown that the molecular data is not consistent with sudden origins. Instead it shows that all of the major animal phyla are related and that their common ancestors probably lived millions of years before the Cambrian explosion. Thus, the evidence indicates deep divergence and the lack of transitional fossils does not prove the non-existence of these ancestral forms.
In order to support his creationist view, Meyer has to discredit the molecular evidence. We've already seen that he has five arguments against the data [Darwin's Doubt: The Genes Tell the Story?]. The first three were: (1) there are no transitional fossils [The Cambrian Conundrum: Stephen Meyer Says (Lack of) Fossils Trumps Genes]; (2) different molecular phylogenies do not agree in all detail [Stephen Meyer Says Molecular Evidence Must Be Wrong Because Scientists Disagree About the Exact Dates]; and (3) different genes evolve at different rates [Stephen Meyer Says Molecular Data Must Be Wrong Because Different Genes Evolve at Different Rates].
None of those arguments are correct and one of them (#3) is just plain silly.
The University of Toronto is sponsoring a "science" festival with three talks tomorrow and Saturday. You have to buy tickets at: tickets.
There's two technology talks and one science talk. I'm going to the only science talk at the science festival. There are a bunch of other things going on, see the entire program.
Friday, Sept. 27th 7pm– "Human Exploration of Space: 50 Years and Counting": Space Shuttle veteran and first Canadian on board the International Space Station, Julie Payette
“High achiever” barely begins to describe Julie Payette. Masters degree in engineering, pilot, IBM engineer, Officer of the Order of Canada, singer with symphonies in Montreal, Toronto, and Switzerland, conversant in six languages, and now Director of the Montreal Science Centre. Oh, did we mention she was orbiting the Earth, using a giant robot arm to build a space station by the time she was 35? Julie will kick off the festival by sharing her unique insights into the past, present, and future of human space exploration.
Friday, Sept. 27th 8pm– "Brave Genius: Jacques Monod, Chance, and our Place in the Universe": Evolutionary biologist and “evo devo” pioneer, Sean Carroll
Biologist and Nobel Laureate Jacques Monod once remarked that “the most important results of science have been to change the relationship of man to the universe, or the way he sees himself in the universe.” Discoveries in molecular biology, evolutionary biology, and geology over the past half-century have profoundly reshaped our picture of human origins, and revealed the enormous role of chance in the fate of life on Earth. Join evolutionary biologist Sean Carroll as he chronicles some of those discoveries through Monod’s eyes, whose own ascent from struggling graduate student to leader within the French Resistance, co-founder of molecular biology, and emergence as a public figure and leading voice of science involved a great deal of chance, and courage.
Saturday, Sept. 28th 7pm– "Postcards from Mars": Mars rover imaging scientist, Jim Bell
Don’t worry if your application to live on Mars was rejected. You can still visit the Red Planet through the spectacular imagery captured by a trio of Mars Rovers—Spirit, Opportunity and Curiosity. Planetary scientist Jim Bell was instrumental in developing cameras and processing images from the three robotic explorers and in his talk “Postcards from Mars”, he’ll share his favorite vistas of our planetary neighbour with you. Through the beauty of these photographs, you’ll see why Bell can be described as a scientist, an explorer and a nature photographer.
Chris DiCarlo talked about fallacies in our class today. We're trying to teach students how to recognize the most important logical fallacies that they are likely to encounter in debates and discussions. He also talked about the importance of consistency and how being caught out as a hypocrite can be devastating to your cause.
Speaking of hypocrisy, the Popular Science website has just banned comments. Apparently they were getting overwhelmed with crackpots and kooks [Why We're Shutting Off Our Comments].
A politically motivated, decades-long war on expertise has eroded the popular consensus on a wide variety of scientifically validated topics. Everything, from evolution to the origins of climate change, is mistakenly up for grabs again. Scientific certainty is just another thing for two people to "debate" on television. And because comments sections tend to be a grotesque reflection of the media culture surrounding them, the cynical work of undermining bedrock scientific doctrine is now being done beneath our own stories, within a website devoted to championing science.
There are plenty of other ways to talk back to us, and to each other: through Twitter, Facebook, Google+, Pinterest, livechats, email, and more.
That's not hypocritical. The hypocrisy comes from Uncommon Descent where someone names "nullasalus" blogged about the Popular Science decisions [Popular Science shuts down comments, citing the presence of dissent from the scientific consensus]. Here's what he/she/it said
Science is not what’s being championed at Popsci.com, nor is ‘bedrock scientific doctrine’ challenged by dissent. Consensus is. Orthodoxy is. Likewise, being ‘politically motivated’ with regards to science is not a problem – it is having political, social and even religious views that PopSci has decided are unacceptable. Dialogue and discussion is welcomed by the self-appointed champions of science – if and only if it results in an outcome they favor. If they suspect it doesn’t, then the dialogue and discussion is over.
Why, it’s almost as if science was never really the concern to begin with.
I was going to make a comment but I can't because I've been banned. Apparently the people at Uncommon Descent have decided that my views are unacceptable. I also can't make any comments over on Evolution News & Views because they don't allow comments.
That's what hypocrisy looks like.
Bradley Monton is a Professor in the Department of Philosophy at the University of Colorado at Boulder. On his website he says he specializes in the philosophy of time, philosophy of religion, philosophy of science (especially physics). He doesn't appear to have any expertise in biology or evolution but he's interested in Intelligent Design Creationism.
A few years ago (2009) he published a book with a provocative title: Seeking God in Science: An Atheist Defends Intelligent Design. Normally I wouldn't pay much attention to such a book but Salvo magazine ("Society, Sex, Science") just published an interview with him [Beyond Belief (or the Lack Thereof)]. It ain't pretty.
Last week's molecules were guanine and adenine. Everyone should have known these structures but only undergraduate Zhimeng Yu got it right! [Monday's Molecule #215].
You probably didn't memorize the structure of this week's molecule but you should be able to recognize it and check your answer in a textbook or on the web. What it is it? (I don't know why it has a gray background. Can anyone help? Fixed.)
Email your answers to me at: Monday's Molecule #216. I'll hold off posting your answers for at least 24 hours. The first one with the correct answer wins. I will only post the names of people with mostly correct answers to avoid embarrassment. The winner will be treated to a free lunch.
There could be two winners. If the first correct answer isn't from an undergraduate student then I'll select a second winner from those undergraduates who post the correct answer. You will need to identify yourself as an undergraduate in order to win. (Put "undergraduate" at the bottom of your email message.)
I finally got to take the quiz at Dialect Quiz & Survey. The server is often overloaded and answering the 140 questions takes more than one hour because of the slow server.
My dialect is most like that of Buffalo NY, which is hardly a surprise since it's the closest American city to Toronto. (I grew up in Ottawa but I don't have much of an Ottawa Valley accent.)
I've been dealing with Intelligent Design Creationists for over twenty years. I've spent a lot of time addressing their scientific misconceptions and trying to explain where they've gone wrong. A few years ago, for example, I posted a whole series of article on Jonathan Wells' book The Myth of Junk DNA. A few weeks ago I explained why Jonathan McLatchie was wrong about pseudogenes.
Lately, I been focusing on one of the chapters in Darwin's Doubt—it's the one on molecular evolution and I know something about that subject. It has been pretty easy to show why Mayer is wrong about his conclusions.
That's why it's so frustrating to read what journalist Tom Bethell said the other day on Evolution News & Views (sic) ["What Is the World Really Like?" Darwinism, Materialism, and How They Relate].
The explicit materialism of the Darwinians is the mirror image of creationism. Creationists are easy for scientific materialists to rebut, because the materialists can say, "That is just your belief. We don't have to accept that." In a parallel way, we can say to the materialists: "That is just your belief. We don't have to accept that. And it is the real basis of your evolutionism."
In between the Creationists and the Materialists we encounter the scientific evidence that makes the materialist position increasingly improbable -- the evidence that Stephen Meyer recently presented in Darwin's Doubt: information theory, insufficiency of the fossil record, epigenetics, complexity of life at the molecular level, and so on.
Increasingly, it seems to me, the Darwinians are responding to this science by saying (in effect): "Bah! We won't read that! It's creationism in disguise." They get graduate students like Nick Matzke, or incompetents like John Farrell (in National Review of all places), to do the work for them. All along the Darwinists have found that their materialism has allowed them to lie back and relax without really bothering to study the evidence.
Now that may be changing. They are being put in a position where they just might have to hit the books. I suspect it is not a prospect that they relish.
Keep in mind that this is written by a man who denies that humans cause global warming and denies that HIV causes AIDS.
He has no idea what evidence looks like.
You've probably noticed that in addition to being stupid most IDiots are not very respectful of scientists (i.e. Darwinists). William J Murray1 explains why religious people have to be mean and nasty [Can We Afford To Be Charitable To Darwinists?].
I used to be one that diligently attempted to provide Darwinists charitable interaction. I tried not to ridicule, demean, or use terms that would cause hurt or defensive feelings. My hope was that reason, politely offered, would win the day. My theistic perspective is that returning the bad behavior I received at sites like TSZ would be wrong on my part. I thought I should stick to politely producing logical and evidence-based exchanges, regardless of what Darwinists did. I note that several others here at UD do the same. Lately, however, I’ve come to the conclusion that what I’m attempting to do is the equivalent of bringing a knife to a gun fight; polite reasoning with Darwinists, for the most part, is simply setting up our own failure. It’s like entering a war zone with rules of engagement that effectively undermine a soldier’s capacity to adequately defend themselves, let alone win a war. While pacifism is a laudable idea, it does not win wars. It simply gives the world to the barbarians.
And that’s the problem; a lot of us don’t realize we’re in a war, a war where reason, truth, religion and spirituality is under direct assault by the post-modern equivalent of barbarians. They, for the most part, have no compunction about lying, misleading, dissembling, attacking, blacklisting, ridiculing, bullying and marginalizing; more than that, they have no problem using every resource at their means, legal or not, polite or not, reasonable or not, to destroy theism, and in particular Christianity (as wells as conservative/libertarian values in general). They have infiltrated the media, academia and the entertainment industry and use their influence to generate narratives with complete disregard for the truth, and entirely ignore even the most egregious barbarism against those holding beliefs they disagree with.
Wars are what happen when there is no common ground between those that believe in something worth fighting for. There is no common ground between the universal post-modern acid of materialist Darwinism and virtually any modern theism. There is no common ground between Orwellian statism-as-God and individual libertarianism with freedom of (not “from”) religion. There is only war. One of the unfortunate problems of war is that certain distasteful methods must be employed simply because they are the only way to win. In this war, in a society that is largely a low-information, media-controlled battleground, logic and reason are, for the most part, ineffective. The truth is ineffective because it is drowned out by a concerted cacophony of lies, or simply ignored by the gatekeepers of low-information infotainment. What has been shown effective is the Alinsky arsenal of rhetoric, emotional manipulation, and narrative control.
I would find it distasteful to pick up a gun in a ground war and have to shoot others to defend my family and way of life, but I would do so. Should I not pick up Alinsky’s Rules for Radicals and employ the weapons of my adversaries, if it is the most effective way – perhaps the only way – of winning the cultural war? There comes a point in time where all the high ground offers is one’s back against the precipice as the barbarian horde advances.
I understand where he's coming from. He's a good Christian who advocates "lying, misleading, dissembling, attacking, blacklisting, ridiculing, bullying and marginalizing" because that's what his opponents do. (And because his versions of truth, logic, and reason have proven to be ineffective.)
BTW, did you notice that he forgot to pretend that the Intelligent Design Creationist movement was all about science, not religion? Oops.
Note to William Murray: If you really were trying "not to ridicule, demean, or use terms that would cause hurt or defensive feelings" then why did you call us "Darwinists"?
1. I assumed that he was the Baptist minister but apparently it's a different William J. Murray.
I read everything posted on Uncommon Descent and Evolution News & Views. These are the most important blogs for learning about Intelligent Design Creationism. The posts on those two blogs represent the very best that Intelligent Design Creationism has to offer. Their best minds are behind the posts.
Here, for example, is Denyse O'Leary in action: Turns out some Texas media DID believe Texas bans discussion of evolution.
... epigenetics is to Darwin’s darlings what relativity and quantum mechanics are to Newtonian physics, only worse, much worse. Newtonian physics was useful within its scale. Darwin’s magical mechanism of natural selection is more like phlogiston, which supposedly produced fire the way Darwinism supposedly produces mind from mud.
And if nothing really happens that way, what becomes of Darwin’s magical mechanism? It’s phogliston, the substance that need not exist!
Seriously, that's the best of the best?
You have to imagine that there are some Intelligent Design Creationists with a modicum of intelligence. Why aren't they speaking up to muzzle people like Denyse O'Leary? She's an embarrassment to their cause.
Stephen Meyer is promoting the idea that God made all the various types of animals over a short period of time about 530 million years ago. The molecular data refutes that speculation because it shows that the various phyla share common ancestors and many of those ancestors appear long before the Cambrian Explosion.
This data creates a serious problem for the IDiots so they have to discredit it in order to dismiss it. As we've seen in earlier posts, Meyer argues that the molecular data is wrong because: (a) there are no transitional fossils, and (b) different molecular phylogenies do not agree in all detail [see The Cambrian Conundrum: Stephen Meyer Says (Lack of) Fossils Trumps Genes and Stephen Meyer Says Molecular Evidence Must Be Wrong Because Scientists Disagree About the Exact Dates]. He has five anti-evolution arguments altogether [Darwin's Doubt: The Genes Tell the Story?]. The third one is that different genes evolve at different rates.
Yesterday I attended a meeting organized by the Ontario Ministry of Education. The theme was From Great to Excellent: The Next Phase in Ontario's Education Strategy. The idea was to promote widespread consultation before the Ontario government releases its new plan for education reform next year.
I was attending on behalf of my friend Chris DiCarlo who had to be out of town. He (and I) are promoting the concept of critical thinking; specifically, the idea that it needs to be explicitly taught in a high school philosophy course.
The Minister of Education (Liz Sandals) and several of the senior members of her ministry were there. They told us that today's students are facing unprecedented changes and that the Ontario education system has to change in order to cope. They were mostly thinking about technological change and the possibility that today's students would have new types of jobs and careers.
I'm certain that we can improve our education system but I'm not sure it's helpful, or even correct, to focus on the idea that the next generation will have to cope with situations we never faced in the past. If we could show that our existing education system did a pretty good job of preparing students for change then maybe we should turn our attention to problems other than job training and technological innovation?
I'm indebted to Veronica for telling me about this petition. I stole the title of her post: La Place du Crucifix de l’Assemblée Nationale Est dans un Musée.
Sign this petition if you think the crucifix should be removed from the Quebec National Assembly.
Stephen C. Meyer believes that the rapid appearance of complex, primitive, animals in the Cambrian cannot be explained without invoking God. The fact that there are no obvious transitional forms in the fossil record means, to him, that those transitional forms don't exist and God must have created all those primitive animals over a short period of time. Presumably, God then let them evolve naturally for the next 530 million years. (Meyer isn't very clear about this.)
Scientists looked at the molecular data in order to test the hypothesis that the Cambrian animals appeared suddenly in a very rapid radiation. The molecular data did not show such a rapid radiation. The overall pattern was consistent with branching evolution spread out over many millions of years. The diagrams that Meyer shows in his book are similar to the figure shown below from Erwin et al. (2007).
