tag:blogger.com,1999:blog-37148773.post3285135373202803756..comments2024-03-27T14:50:47.345-04:00Comments on <center>Sandwalk</center>: What did ENCODE researchers say on Reddit?Larry Moranhttp://www.blogger.com/profile/05756598746605455848noreply@blogger.comBlogger18125tag:blogger.com,1999:blog-37148773.post-64122533207299433802017-02-13T12:08:07.033-05:002017-02-13T12:08:07.033-05:00liarsfordarwin wrote: "...John Rinn ... poly...liarsfordarwin wrote: "...John Rinn ... polycomb repression ... That seems to fit the bill"<br /><br />Well, thanks for the pointer leading me off to some interesting googling and pdf-ing. I'm far from an expert on this stuff. But no, I don't think that does 'fit the bill'. Most of what I read about were descriptions of effects rather than of functions. And the most clearly functional pieces of the story seemed to be the fruits of research that started well before ENCODE and that were in no way inspired by ENCODE.<br /><br />Still, my reading led me to this article:<br /><br />https://dspace.mit.edu/openaccess-disseminate/1721.1/58204<br /><br />... which is interesting for several reasons.<br />(1) Rinn is one of the authors.<br />(2) It seems to endorse Larry's argument that 95% of the transcripts that ENCODE called functional really ARE junk.<br />(3) Within the remaining 5% they found about a thousand examples of transcribed non-coding RNAs which probably do have a function, since they are conserved in evolution.<br /><br />The project and methods in that paper strike me a much more fruitful approach to research than ENCODE.Jim Menegayhttps://www.blogger.com/profile/06217224823822142530noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-51591093944262215232017-02-12T16:28:33.805-05:002017-02-12T16:28:33.805-05:00Sal Cordova says,
Well, thanks for looking at Bre...Sal Cordova says,<br /><br /><i>Well, thanks for looking at Brenda Andrews work at your University. </i><br /><br />You're welcome. <br /><br />Believe it or not, I actually knew about Brenda's work before I watched the video. :-) <br /><br />I remember when she was a graduate student.Larry Moranhttps://www.blogger.com/profile/05756598746605455848noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-9074010337847485942017-02-12T15:11:11.565-05:002017-02-12T15:11:11.565-05:00THE FOREIGN DNA AMOUNT ARGUMENT
Strange celebriti...<b>THE FOREIGN DNA AMOUNT ARGUMENT</b><br /><br />Strange celebrities turned politicians,<br />May sadly lament 'so-called' judges,<br />But scientists with truthful missions<br />Should not engage in sim'lar fudges.<br /><br />The so-called junk DNA that some count,<br />As actor main in Haldane's rule,<br />A "question of DNA amount."<br />Say Naviera-Masides' fine school.<br /><br />All that so-called junk,<br />Acts with due celerity,<br />How can it be just bunk,<br />When endows hybrid sterility?<br /><br />Set Darwin's day on stage<br />To Haldane's rule add further <a href="http://post.queensu.ca/~forsdyke/haldane1.htm" rel="nofollow">page!</a><br />Donald Forsdykehttps://www.blogger.com/profile/18038104286639798795noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-33865163723961715722017-02-12T12:36:55.745-05:002017-02-12T12:36:55.745-05:00Well, thanks for looking at Brenda Andrews work at...Well, thanks for looking at Brenda Andrews work at your University. <br /><br />The may be little or no detectable effect with single-gene knockout, but there is often detectable effect when there is double or triple knockout. What this means was that when Dr. Andrews started from a gene dictionary of 6000 yeast genes, the space of double-knockouts was 6000 squared which is a whopping 36,000,000 combinations that could only be surveyed high throughput assays. Triple knockouts would be on the order of 6000 cubed or 2.1 x 10^11 combinations. But what can't be denied is that she was able to elucidate cooperative function of genes that couldn't be deduced via single knockout. As she said, Eukaryotic genomes are heavily buffered.<br /><br />Now, one can only imagine what would be needed to do something similar with the coding and non-coding elements. Which would support your claim:<br /><br />"It should keep the money flowing for decades."<br /><br />How about centuries? :-) <br />Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-37148773.post-56653744867850105812017-02-12T12:02:04.381-05:002017-02-12T12:02:04.381-05:00We are mostly interested in parts of the genome th...We are mostly interested in parts of the genome that are transcribed at some low level (less than one RNA per cell), and in sites that bind transcription factors. <br /><br />We can focus on those sites that are not conserved—this is probably 99% of the sites. <br /><br />The question before us is, do these sites have a biological function? One way to answer the question is to knock out (delete) the site and ask if there's any observable effect. Brenda Andrew's work with yeast cells tell us that such deletions often have no detectable effect even when known genes are removed.<br /><br />This result is fantastic from the perspective of ENCODE researchers. It means that the hypothesis of function can't be easily refuted by a simple knockout experiment. <br /><br />It should keep the money flowing for decades. <br /><br />(They've already convinced themselves that lack of sequence conservation as isn't going to count as falsification.)<br /><br />The real problem here is the assumption of function that seems to be the unanimous assumption of all ENCODE labs. It places the onus on opponents to prove that the site in question has no function. But, as we all know, proving the negative is an almost impossible goal. <br /><br />That's the wrong way to do science. The null hypothesis should be "no function." The onus should be on those who propose a largely functional genome to prove their case by finding function. The default explanation is that the genome is mostly junk. (There is plenty of evidence to support this claim.) So far ENCODE has failed to show that most of the genome has a biological function so the default explanation has not been falsified. Larry Moranhttps://www.blogger.com/profile/05756598746605455848noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-53656841494138793612017-02-12T09:55:19.322-05:002017-02-12T09:55:19.322-05:00That's my impression too. It looks like they h...That's my impression too. It looks like they haven't been paying attention to any of the criticisms. Larry Moranhttps://www.blogger.com/profile/05756598746605455848noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-77260421048824947952017-02-12T09:38:14.261-05:002017-02-12T09:38:14.261-05:00It seems from this summary that Encode researchers...It seems from this summary that Encode researchers have not learnt from their previous claim that most of the genome was functional. Of course there are transposable elements that have been co-opted; of course not everything in our genomes are protein-coding genes; of course there is functionally relevant alternative splicing. However, there is no evidence to infer that much of our genome is "functional". On the contrary, the evolutionary patterns we see suggest it is not. <br /><br />Very frequently tissue-specificity is used to demonstrate functionality, as for example in the context of alternative splicing. This makes no sense. We know our genome is read differently in different cells, thanks to epigenetics, splicing factors, transcription factors... It is clear that all this "real" tissue specificities can result in tissue-specific noise. Hence, although tissue-specificity can be a starting point, it shouldn't be taken as confirmation of functional relevance.Federico Abascalhttps://www.blogger.com/profile/10122081847965890500noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-79861885370315505212017-02-12T08:12:41.402-05:002017-02-12T08:12:41.402-05:00593 research projects and counting that used ENCOD...<i>593 research projects and counting that used ENCODE data in the understanding and treatment of disease, which is more than I can say for what the 170 million dollars wasted on the untestable phylogenies of the tree-of-life project did for the advancement of medical science.</i><br /><br />So could you kindly remind me of the major contributions to medical science made by Intelligent Design Creationist research? Because for some reason it slipped my mind and I can't recall a single one. Faizal Alihttps://www.blogger.com/profile/00937075798809265805noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-37512652145961848482017-02-12T05:05:45.579-05:002017-02-12T05:05:45.579-05:00"No it wouldn't, you couldn't falsify..."No it wouldn't, you couldn't falsify that hypothesis."<br /><br />True, but it would motivate attempts at falsifying the junkDNA hypothesis, and until we cure every genomically associated disease on the planet (like cancer), we have plenty of reason to keep looking. Besides, that's the sentiment in the medical community that's well-entrenched long before ENCODE made their infamous 80-100% functionality statement. Goes to show they don't care that much about the C-value paradox, and won't let evolutionary biologists tell them what they can and can't discover about the genome. <br /><br />"in principle a single observation would falsify the junk-null. For example, a knockout experiment."<br /><br />But you can't do this with simple 1-gene at a time knockout experiments, but multi-knockout experiments since Eukaryotic genomes are "highly buffered" (to use the phrase of one of Larry's Colleagues at University of Toronto, Brenda Andrews, who was part of the ENCODE planning session in 2015.)<br /><br />She alludes to why the ENCODE approach and data aggregation is probably going to be the required approach to understanding genome function.<br /><br />https://www.youtube.com/watch?v=aeDHuY5lUek<br /><br />https://www.genome.gov/Multimedia/Slides/ENCODE015/25_Andrews.pdf<br /><br />Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-37148773.post-43860574522873198192017-02-12T04:48:50.040-05:002017-02-12T04:48:50.040-05:00" Stories that go: (1) No one suspected this ..." Stories that go: (1) No one suspected this genome segment had a function, (2) but then ENCODE suggested that is does, (3) so someone checked it out and, (4) OMG, there is a clear cut and essential function there, the mechanism of which will be described in all of the next generation of textbooks."<br /><br /><br />One of the occasional ENCODE experimenters, John Rinn at the Broad Institute Harvard, in 2007 studied the differential RNA expression patterns that Dan Graur is so keen to dismiss as noise. One RNA in particular was expressed in skin cells below the human wasteline but not above it. Rinn discovered the first trans acting (inter-chromosome) RNA that regulated DNAs on other chromosomes through the polycomb repression complex. Rinn's discovery was one of the most spectacular ever published in the journal Cell. That seems to fit the bill.<br /> <br /><br />"Are there any ENCODE success stories?"<br /><br />593 research projects and counting that used ENCODE data in the understanding and treatment of disease, which is more than I can say for what the 170 million dollars wasted on the untestable phylogenies of the tree-of-life project did for the advancement of medical science. See here:<br /><br />https://www.encodeproject.org/search/?type=Publication&published_by=community&categories=human+disease<br /><br />That's why there will be now the PscyhoENCODE project. :-)<br /><br />http://www.nature.com/neuro/journal/v18/n12/full/nn.4156.html<br /><br />But if you want to see why there will be so much demand for ENCODE data and functional genomics, particularly ENCODE 4, take a look at this from the ENCODE planning session in 2015. This is a presentation by Brenda Andrews, University of Toronto:<br /><br />https://www.youtube.com/watch?v=aeDHuY5lUek<br /><br />https://www.genome.gov/Multimedia/Slides/ENCODE015/25_Andrews.pdf<br /><br /><br />Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-37148773.post-40963064314130103732017-02-12T03:32:03.634-05:002017-02-12T03:32:03.634-05:00"But that said, since 90% of disease implicat...<i>"But that said, since 90% of disease implicated SNPs are non-coding regions, it would seem a reasonable extrapolation to adopt 100% functionality as a working hypothesis till proven otherwise."</i><br /><br />No it wouldn't, you couldn't falsify that hypothesis. You could always just reason ad-hoc that there is some hitherto undiscovered circumstance where your piece of DNA has some obscure functional role you just haven't gotten around to test or discover yet. <br /><br />Whereas with a junk null, in principle a single observation would falsify the junk-null. For example, a knockout experiment.<br /><br />Besides, mutations in junk can easily cause otherwise nonfunctional reasons to "look like" a functional region and produce interfering gene products. <br /><br />As usual you've got all this shit backwards. Which is, I guess, to be expected from a person working backwards from his emotionally desired conclusion that life was instantaneously wished into existence through a magic spell, in perfect form, about 6000 years ago. Mikkel Rumraket Rasmussenhttps://www.blogger.com/profile/07670550711237457368noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-10426304004422345592017-02-11T21:48:57.537-05:002017-02-11T21:48:57.537-05:00The spin doctors, hard at work! Like this above re...The spin doctors, hard at work! Like this above response which I have edited to point out the spin.<br />"Great question! Only 2% of our genome are genes that code for protein. Around 45% of our genome is actually made of what's called repeats, many of them viruses that were inserted into our genome. Various cool studies show that BEGIN SPIN several of them END SPIN have adapted new functions that made them 'stay' in our genome — like becoming parts of other genes or adopting a gene regulatory function (instructing genes when, where and at what levels to turn on). As for the remaining 53%, we see that BEGIN SPIN a lot of it END SPIN has regulatory function and other functions which we still don't know and which are fascinating in my mind to uncover."Marcolihttps://www.blogger.com/profile/00542204027681831657noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-13882586586755237142017-02-11T21:39:58.048-05:002017-02-11T21:39:58.048-05:00liarsfordarwin said,
I think they don't reall...liarsfordarwin said,<br /><br /><i>I think they don't really care how much of the genome is functional. That's not the mission of ENCODE.</i><br /><br />Three hours later he said,<br /><br /><i>That statements says nothing of what percentage of the genome ENCODE is supposed to find as functional. They just have to identify all the functional elements, whatever percentage of the genome they are.</i><br /><br /><br />I'm begining to see why Sal Cordova prefers to be called liarsfordarwin. <br />Larry Moranhttps://www.blogger.com/profile/05756598746605455848noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-22907852129999365522017-02-11T19:17:32.776-05:002017-02-11T19:17:32.776-05:00I wonder if they would have received the $31 milli...I wonder if they would have received the $31 million grant if they had said "All available evidence strongly suggests that the vast majority of non-coding DNA is junk, and we believe that is true. But we want to check, just to make sure. Faizal Alihttps://www.blogger.com/profile/00937075798809265805noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-34404208014801811032017-02-11T19:09:04.328-05:002017-02-11T19:09:04.328-05:00I would expect that we would have some ENCODE succ...I would expect that we would have some ENCODE success stories by now. Stories that go: (1) No one suspected this genome segment had a function, (2) but then ENCODE suggested that is does, (3) so someone checked it out and, (4) OMG, there is a clear cut and essential function there, the mechanism of which will be described in all of the next generation of textbooks.<br /><br />Are there any ENCODE success stories? I don't recall reading of any.Jim Menegayhttps://www.blogger.com/profile/06217224823822142530noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-48805357915393158852017-02-11T18:54:40.341-05:002017-02-11T18:54:40.341-05:00"The National Human Genome Research Institute..."The National Human Genome Research Institute (NHGRI) launched a public research consortium named ENCODE, the Encyclopedia Of DNA Elements, in September 2003, to carry out a project to identify all functional elements in the human genome sequence"<br /><br />That statements says nothing of what percentage of the genome ENCODE is supposed to find as functional. They just have to identify all the functional elements, whatever percentage of the genome they are. Furthermore, if "functional" means biochemical or physical activity (aka transcription, serving as spacers, scaffolds, etc.) then ENCODE is doing their job as far I can tell.Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-37148773.post-2441046845484873722017-02-11T18:21:40.644-05:002017-02-11T18:21:40.644-05:00Sal Cordova says,
I think they don't really c...Sal Cordova says,<br /><br /><i>I think they don't really care how much of the genome is functional. That's not the mission of ENCODE.</i><br /><br />From <a href="https://www.genome.gov/10005107/encode-project/" rel="nofollow">The ENCODE Project: ENCyclopedia Of DNA Elements</a><br /><br /><i>The National Human Genome Research Institute (NHGRI) launched a public research consortium named ENCODE, the Encyclopedia Of DNA Elements, in September 2003, to carry out a project to identify all functional elements in the human genome sequence.</i>Larry Moranhttps://www.blogger.com/profile/05756598746605455848noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-16615865369838187402017-02-11T15:52:58.044-05:002017-02-11T15:52:58.044-05:00"They just received 31.5 million dollars to c..."They just received 31.5 million dollars to continue their search for functional regions in the human genome."<br /><br />That's an annual grant as far as I can tell, even more than the 20 million I usually see per year. In 10 years that could be another 300 million. Whoa!<br /><br />I think they don't really care how much of the genome is functional. That's not the mission of ENCODE.<br /><br />But that said, since 90% of disease implicated SNPs are non-coding regions, it would seem a reasonable extrapolation to adopt 100% functionality as a working hypothesis till proven otherwise.<br /><br />If only 15% of the genome is functional and 85% is junk, unless we know in advance exactly which 15% to focus on and 85% to ignore, then it is pointless to defund the work of ENCODE, and the 100% functionality hypothesis is good enough to do their job. There would be an uproar in the medical research community to do otherwise.<br /><br />What set of experiments for ENCODE 4 do you want to defund? Hi-C, Chip-Seq, RNA-seq, WGBS, and about 40 or so other experiments?<br /><br />The 100% functionality figure is probably the intuitive sentiment of most medical researchers. The reason for this? When I was at ENCODE 2015, medical researcher after researcher said to the effect, "GWAS studies has shown the disease I'm studying is strongly associated with non-coding regions". That sort of data, as far as medical researchers are concerned, takes precedence over whatever evolutionary biologists have to say. <br /><br />Anonymousnoreply@blogger.com