tag:blogger.com,1999:blog-37148773.post1587549853305534931..comments2024-03-27T14:50:47.345-04:00Comments on <center>Sandwalk</center>: How many human protein-coding genes are essential for cell survival?Larry Moranhttp://www.blogger.com/profile/05756598746605455848noreply@blogger.comBlogger18125tag:blogger.com,1999:blog-37148773.post-91321908867324205462015-12-12T14:15:43.752-05:002015-12-12T14:15:43.752-05:00Well, I'm sure your expert opinion means the w...Well, I'm sure your expert opinion means the world to Larry, Vincent Torley. But are you conceding that those other 445,000 "genes" are junk? If so, shouldn't you be trying to convince your fellow creationists of that? Many of them still think all of the human genome is functional. Faizal Alihttps://www.blogger.com/profile/00937075798809265805noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-12645384855562512852015-12-12T12:30:47.762-05:002015-12-12T12:30:47.762-05:00Hi Professor Moran,
Thank you very much for your ...Hi Professor Moran,<br /><br />Thank you very much for your reply. I think your figure of 5,000 functional RNA genes is a fair one.Vincent Torleyhttps://www.blogger.com/profile/18275683804952032659noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-5098962344508000012015-12-12T10:45:13.620-05:002015-12-12T10:45:13.620-05:00"In other cases there are different genes for..."In other cases there are different genes for cytoplasmic and mitochondrial versions of the enzyme. In those cases (e.g. malate dehydrogenase) it's very unlikely that the two enzymes can substitute for one another."<br /><br />Has anyone looked to see if dual targeting, say, of the purported mitochondrial isoforms, can be operative here? For example, if but a few percent of the transcriptional output of the gene encoding the mitochondrial isoform ended up in the form of a cytoplasmic enzyme, would this be enough to overcome a deficit in the expression of the gene encoding the cytoplasmic isoform? Perhaps, akin to splicing errors, import is not so perfect such that some protein/enzyme ends up inappropriately localized.<br /><br />Lots of food for thought is buried in these papers. At many different levels. I sort of like how the two studies, their discrepancies and agreements, and surprising observations such as are pointed out in blog essay, challenge some (or much) of what I often take for granted.<br /><br />Arthttps://www.blogger.com/profile/15136555410759022118noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-73167717448021025122015-12-12T10:44:11.881-05:002015-12-12T10:44:11.881-05:00@Ed
Thanks for the reference. I wasn't aware ...@Ed<br /><br />Thanks for the reference. I wasn't aware of the enzyme you call ATP-citrate lyase [= ATP citrate synthase <a href="http://www.chem.qmul.ac.uk/iubmb/enzyme/EC2/3/3/8.html" rel="nofollow">EC 2.3.3.8</a>]. <br /><br />It doesn't explain why the cells in this study appear to be missing some important enzymes. (BTW, it's very unlikely that the cells are actually missing those enzymes. The fact that the genes appear to be nonessential is likely an artifact of the screening procedures.) <br /><br />But even if it's true that aberrant cells (e.g. cancer cells) have a strange metabolism, this just confirms that the studies aren't really defining all of the cell-essential genes in normal human cells. Larry Moranhttps://www.blogger.com/profile/05756598746605455848noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-21524527595505842192015-12-12T10:24:48.069-05:002015-12-12T10:24:48.069-05:00Some of them are gene families—the hexokinases are...Some of them are gene families—the hexokinases are an example. You are correct (my bad!) in saying that two or more of these genes may be expressed in the cells in culture so that no single gene is "essential."<br /><br />Some of the others aren't gene families but subunits of a multimeric protein. <br /><br />In other cases there are different genes for cytoplasmic and mitochondrial versions of the enzyme. In those cases (e.g. malate dehydrogenase) it's very unlikely that the two enzymes can substitute for one another. Larry Moranhttps://www.blogger.com/profile/05756598746605455848noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-83533402160856642582015-12-12T09:55:11.998-05:002015-12-12T09:55:11.998-05:00Vincent Torley writes,
It appears that Dr. Richa...Vincent Torley writes,<br /><br /><i> It appears that Dr. Richard Sternberg disagrees with you.</i><br /><br />Stop the presses! Imagine that! An Intelligent Design Creationist who disagrees with me! Wonders never cease.<br /><br />Vincent, you are reasonably intelligent so it continues to surprise me that you trust the information being spewed by ID proponents. You should know better. <br /><br />There are lots and lots of RNAs made by various human cells. We know for certain that some of them are nonfunctional; therefore, they are not specified by "genes." <br /><br />What we don't know for certain is how many of them are functional. The onus is on those who claim functionality to prove that the transcripts have a function. So far only a few hundred transcripts, at most, have been shown to have a function. That means only a few hundred "genes" for noncoding RNAs. There's no evidence to suggest that this number will get much larger in the future. <br /><br />I'm arbitrarily choosing 5,000 to make sure I'm in the optimistic range of predictions. <a href="http://useast.ensembl.org/Homo_sapiens/Info/Annotation?redirect=no" rel="nofollow">Ensembl</a> (GRCh38.p5) predicts 25,000 but they're being ridiculous. <br /><br />Here's the reference to the paper that Richard Sternberg mentioned.<br /><br /><b>Rederstorff, M., Bernhart, S.H., Tanzer, A., Zywicki, M., Perfler, K., Lukasser, M., Hofacker, I. L., and Hüttenhofer, A. (2010)</b> RNPomics: defining the ncRNA transcriptome by cDNA library generation from ribonucleo-protein particles. Nucl. Acid. Res. 38:e113-e113. [<a href="http://dx.doi.org/10.1093/nar/gkq057" rel="nofollow">doi: 10.1093/nar/gkq057</a>]<br /><br />The authors are fully aware of the problem of identifying function. The decided to look at how many of the transcripts formed RNP particles. This is an indication of function. They found several hundred potentially functional RNAs. <br /><br />Vincent, you need to learn to be more skeptical of your fellow ID proponents. Not all of them are wrong all of the time but their track record is sufficiently bad that it should make you pause before believing them.Larry Moranhttps://www.blogger.com/profile/05756598746605455848noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-3538130194334443852015-12-12T09:17:57.714-05:002015-12-12T09:17:57.714-05:00Larry, I am a bit confused by the your criticisms ...Larry, I am a bit confused by the your criticisms and by figures you put in this essay. Specifically, you seem to be saying that these studies (at least two of them - the Cell paper is infuriating in the way it hides, or does not make available, most of the information and results most people would like to see) suggest that cultured cells can make do without core metabolic pathways. However, in the two figures you show, it looks like the relevant enzymes are encoded by gene families. I would take home from this the likelihood that purported cell- or tissue- specific genes and enzyme isoforms are not so specific, such that knock-downs or knock-outs of most of the individual genes involved have little effect because other genes can pick up the slack, so to speak. <br /><br />Have I missed something here?Arthttps://www.blogger.com/profile/15136555410759022118noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-76112223628666955582015-12-12T09:09:54.660-05:002015-12-12T09:09:54.660-05:00Vincent, have you read the paper by Rederstorff et...Vincent, have you read the paper by Rederstorff et al.? I don't think it supports Sternberg's claims. Indeed, it is much closer to Dr. Moran's estimate than to Sternberg's.Arthttps://www.blogger.com/profile/15136555410759022118noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-53282835258924175852015-12-12T08:35:04.592-05:002015-12-12T08:35:04.592-05:00Hi Professor Moran,
You write that the human geno...Hi Professor Moran,<br /><br />You write that the human genome contains about 5,000 genes that specify for functional RNAs. It appears that Dr. Richard Sternberg disagrees with you. On an Evolution News and Views post (March 12, 2010), he writes: "While there are ~25,000 protein-coding genes in our DNA, the number of RNA-coding genes is predicted to be much higher, >450,000," although he adds that the latter "range in length from being quite short--only 20 or so genetic letters--to being millions of letters long." To support his claim, he references the following source: Rederstorff M, Bernhart SH, Tanzer A, Zywicki M, Perfler K, Lukasser M, Hofacker IL, Hüttenhofer A. 2010 (In Press). RNPomics: Defining the ncRNA transcriptome by cDNA library generation from ribonucleo-protein particles. Nucleic Acids Research.<br /><br />Would you care to comment? Are you saying that only 5,000 of these 450,000 genes are functional?<br />Vincent Torleyhttps://www.blogger.com/profile/18275683804952032659noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-78415498896409645462015-12-11T10:41:54.382-05:002015-12-11T10:41:54.382-05:00Acetyl-CoA is probably coming from ATP-citrate lya...Acetyl-CoA is probably coming from ATP-citrate lyase which we see to be expressed at very high levels compared with similar cell lines that appear to undergo normal oxidative phosphorylation - (a nice review: http://cancerres.aacrjournals.org/content/72/15/3709.long) <br /><br />I worded my previous post carelessly: not *all* the glucose is converted to lactate but that which gets to the bottom of the glycolytic pathway is largely converted into lactate. The pentose phosphate pathway is active and fed by glucose for the formation of nucleotides. Carbons for amino acid synthesis comes from both glutamine and glucose depending on the amino acid in question.Edhttps://www.blogger.com/profile/04881651833189490558noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-27393765732533780312015-12-11T09:41:17.759-05:002015-12-11T09:41:17.759-05:00Another possibility is that some essential genes a...<i>Another possibility is that some essential genes aren't detected in their assay because they only looked at a few generations of survival....</i><br /><br />Can't see the papers right now but that sounds like a real experimental possibility if the authors are compelled to raise the point.<br /><br />SRMhttps://www.blogger.com/profile/07299706694667706149noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-81671206739598555912015-12-11T08:25:14.036-05:002015-12-11T08:25:14.036-05:00Look at the KDH reaction. One of the substrates is...Look at the KDH reaction. One of the substrates is acetyl-CoA. Where does it come from? Is it all due to the breakdown of fatty acids? If so, where do the fatty acids come from? <br /><br />And in your favorite cell line, if all the glucose is converted to lactate then where do the cells get their carbon for making DNA, RNA, and protein? Larry Moranhttps://www.blogger.com/profile/05756598746605455848noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-73080284130679819202015-12-11T08:06:55.389-05:002015-12-11T08:06:55.389-05:00I'm not the least bit surprised that some very...I'm not the least bit surprised that some very important genes are not essential in cells grown in culture in the laboratory. The inducible heat shock genes are a good example. It merely illustrates the fact that genes detected in these assays are a subset of the real core essential genes required in a natural environmennt.<br /><br />However, there are some genes that I expect to be essential in these cells. The fact that the cells can survive without producing or metabolizing glucose doen't seem right to me. The fact that they don't need a complete citric acid cycle doesn't make sense. Where are they getting their energy?<br /><br />Maybe these strange human cells don't need these pathways in their artificial environment. That's one possibility. Another possibility is that some essential genes aren't detected in their assay because they only looked at a few generations of survival and the cells had enough protein to keep them alive for that long after the gene was knocked out. (One of the papers discusses this limitation.)<br /><br />If the cells really don't need these pathways then that's very curious. You can't just dismiss it by saying that it's not a surprise. If true, it IS a surprise.Larry Moranhttps://www.blogger.com/profile/05756598746605455848noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-52534037573141571842015-12-11T08:05:09.492-05:002015-12-11T08:05:09.492-05:00Unfortunately immortalised cells in culture don...Unfortunately immortalised cells in culture don't read the text books and often their metabolism is substantially different from "normal" - especially if they are cells derived from cancer in the first place. Unless one starts labelling metabolites and following them through the cell by means of, for example, NMR metabolomics one doesn't know how the cell is using the metabolites and therefore whether an enzyme is essential or not. <br /><br />In my favourite cell line glucose doesn't enter the TCA cycle at all and is converted to lactate even in normoxia. Glutamine feeds the TCA cycle via glutamate and alpha-ketogluterate. In this specific case, I don't think these cells would be too fussed by deletion of the pyruvate dehydrogenase complex.Edhttps://www.blogger.com/profile/04881651833189490558noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-63737899100326506072015-12-11T05:03:39.086-05:002015-12-11T05:03:39.086-05:00At an intuitive level I understand an "essent...At an intuitive level I understand an "essential" gene to be a gene without which a cell simply cannot grow and divide under any of the "normal" circumstances it lives under. If there's a "natural" circumstance under which it can grow and divide without some particular gene, then I would say that gene isn't essential. Mikkel Rumraket Rasmussenhttps://www.blogger.com/profile/07670550711237457368noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-46127950273957889982015-12-11T04:53:42.350-05:002015-12-11T04:53:42.350-05:00And the very reason why we have been able to survi...And the very reason why we have been able to survive for 60 million years without the GULO gene is that we can obtain enough vitamion C from our diet. Likewise, all animals need vitamin B12, but only bacteria and archaea can synthesise it.Piotr Gąsiorowskihttps://www.blogger.com/profile/06339278493073512102noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-22716793238446516582015-12-11T01:59:57.891-05:002015-12-11T01:59:57.891-05:00Yeah I was thinking the same thing. It's hard ...Yeah I was thinking the same thing. It's hard to talk essentiality in general terms without supplying an environmental context. <br /><br />So heatshock genes aren't essential if the cell isn't heat-shocked. Isn't that just expected?Mikkel Rumraket Rasmussenhttps://www.blogger.com/profile/07670550711237457368noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-11002630067790287082015-12-10T23:09:45.714-05:002015-12-10T23:09:45.714-05:00Lots of organisms survive just fine without many c...Lots of organisms survive just fine without many core metabolism genes. Does that mean that they can survive in minimal media? Of course not. But the real world isn't a minimal medium but a quite rich place. Even humans as a complete organism are auxotrophs for all kinds of things -- it shouldn't surprise anyone in the least that particular cell lines can get away with even fewer metabolism genes than that.Jonathan Badgerhttps://www.blogger.com/profile/04921990886076027719noreply@blogger.com