Path: utzoo!utgpu!watserv1!watmath!att!pacbell.com!ucsd!usc!zaphod.mps.ohio-state.edu!think.com!hsdndev!husc6!Frodo.MGH.Harvard.EDU!Ellington From: Ellington@Frodo.MGH.Harvard.EDU (Deaddog) Newsgroups: bionet.molbio.bio-matrix Subject: Re: Oh foolish supporters of genome sequencing Message-ID: <5708@husc6.harvard.edu> Date: 13 Feb 91 01:41:21 GMT Sender: news@husc6.harvard.edu Organization: Molecular Biology, Mass. General Hospital Lines: 142 References:<9102111908.AA07006@genbank.bio.net> <5695@husc6.harvard.edu> <1991Feb12.180803.1695@ccu.umanitoba.ca> I make several general comments, which I believe pertain to most of the material in Dr. Fristensky's reply: (1) None of the suggested benefits requires the complete sequence of the genome. All of them could be realized by targeted sequencing. (a) For example, domains that are attached to the nuclear matrix can easily be isolated and sequenced. It is unnecessary to clone them all to determine whether they are involved in higher order chromosome structure, or in gene regulation. In fact, a great deal of experimentation has already been done in this area (see, for example, JMB, 200/101, 1988; TIGS, 3/16, 1987; for those who care, the Bodnar reference is J. Theo Biol., 132/479). (b) The interrelationship between speciation and repetitive sequences is well established; see also, for example, Chromosoma, 78/137 (1980). In fact, plants aside, it has been well-studied in the higher apes, including man (EMBO J., 6/1691 (1987), PNAS, 83/3875 (1986)). The very fact that these studies can be done suggests that sequencing the human genome is less than necessary. If you are truly serious about learning about the role of repetitive sequences in evolution, you would do well to do comparative sequence analysis between related organisms (the approach that has already been taken). 2. To the extent that these are worthy goals, they could be carried out in other, more worthy eukaryotes (again, Drosophila and C. elegans leap to mind). 3. No offense, but if you were to write a grant proposal for these ideas ("I would like to sequence the human genome to learn about how interspersed repetitive sequences affect speciation.") you would receive a rotten priority score. As I have said before, I would like to see the human genome initiative in the same pool of grants as the science it purports to do. I do not believe it would stand up to the harsh scrutiny that everyone else is having to endure. 4. You write: > There are literally thousands > of genes for which only 1-10 copies of the transcript are present in the > cell [Okamuro and Goldberg, 1989]. It is only by obtaining a clear view > of what the cell does with these rare transcripts that we will have a > complete understanding of how gene expression results in a differentiated > organism. Can you tell me exactly how the sequence of the human genome will address this problem? I mean, what do you do: find which genes don't have high abundance RNAs and then look for a function for these genes? If so, how do you intend to look for function? And how is it different than just looking for function in the first place without the sequence of the human genome? One example will suffice. Most genes are identified by phenotypes, which for the human genome will mean RFLP mapping. Some genes will be identified by homology to genes found in other higher organisms that we can ethically mutate all to hell, like rats. In neither case is the sequence of the human genome likely to make a difference in determining *function*. I LIKE THE DARWIN ANALOGY! Good show! Let's carry it a little further. Two points: (1) Was seeing the Finches of the Galapagos the only way Darwin could have realized the wonders of natural selection? (Analogy: even if sequencing the human genome will reveal something unknown, is this the only mechanism by which we can know this unknown thing?) Obviously not: Darwin points out how pigeon and dog breeding are beautiful examples of natural selection at work. Once the insight came, the evidence was all around him. Wallace stumbled across natural selection without ever going to the Galapagos. The DATA was there; the insight was not. Think harder, sequence less. (2) If Darwin had gone to the Royal Grantsmaster and said: "I just know I can figure out how organisms change through time; give me a fleet of ships and I will sail to all the corners of the Earth and collect every piece of biological data that I can find in hopes of finding an answer." I submit that the Royal Grantsmaster would have bunged young Charles out on his young ass. The cost of the Beagle was justified because terrestrial exploration had proven profitable to the English time and again (e.g., the New World). Why not include a snot-nosed naturalist? What justification is the genome initiative going to piggyback on? I gave you the examples of the SV40 and chloroplast genomes: these are what you are going to have to take to the Royal Grantsmaster to justify your big project. What have they yielded? And why is sequencing the human genome a better bet than a hundred other bits of proven science (for closure, why sequence the human genome when we can fund Roy Britten and Eric Davidson to tell us all that we desire about reptitive sequences?) Finally, we have: > It seems likely to me > that sequencing the genome will be cost effective, as compared to > hundreds of separate projects to clone individual genes. Oh come now! The separate projects are seldom directed at just "cloning the individual genes." They are directed at "cloning and understanding the individual genes," which is why they are much more useful than the GeeWhiz approach of the genome initiative. In addition, let's say that the average gene of interest is, oh, 10,000 bases in length. For 100 odd genes that would be 1x10E6 bases, as compared to the human genome size of 3.3x10E9. Are you trying to tell me that it will cost more than 100x more to do directed cloning/sequencing of these target genes than it will to do the whole genome (since you must do a sizeable fraction of the genome to be sure of finding most of the target genes)? And that the concommitant knowledge of what the genes actually does not go a long way to actually justifying that cost (knowledge which may or may not be the product of the genome initiative)? > Query: Is Deaddog (Non-woof) really playing devil's advocate here, > challenging supporters of the genome project to justify it in a better > way than has been done up to now? No, I'm really this much of a curmudgeon. Too much is at stake. I don't actually worry so much about starting the human genome project. Hell, Soviet science survived Lysenko. No, I'm worried about what happens when we finish sequencing the genome, and Congress and the public ask us to justify the cost. At least with the "War on Cancer" there wasn't a defined endpoint staring us in the face. When that sad day comes when the headlines blare "100% complete at a cost of N billion!" there is going to be hell to pay. Non-woof (You know, you Matrix-teers aren't really trying. No one's even mentioned "introns" yet, or "heterochromatin," or "gene dosage," or "sub-telomeric sequences," or .... But of course those are all already being studied in established labs fighting desperately for funding, aren't they?)