evolgen

If it’s not human, it’s crap!

Those of us who work on non-human systems often grumble about the total disregard human geneticists (that’s geneticists who study humans, not humans who are geneticists) have toward non-human research (that’s research on non-humans, not non-humans doing research). I get the feeling that plant biologists have the same attitude toward non-plant researchers, and I imagine there is some unwritten chain of superiority wherein you must pay respect to the researchers working on a system “above” you and ignore the research done on a system “beneath” yours — and, yes, I realize the higher and lower thing is bullshit.

Now for a specific example: Much work has been done in the area of genome rearrangements using non-human systems. A lot of this work has been done in Drosophila, but the human geneticists often neglect this body of work when discussing the recently discovered plethora rearrangements in the human genome (ie, this and this). A recent paper in PNAS exemplifies this behavior. Granted, the paper is from a group that “has focused on the study of chromosomal rearrangements in the bacterial genome”, and they’ve only recently begun studying the human genome. But that’s not excuse to not be familiar with the Drosophila literature that predates any other studies of chromosomal rearrangements.

The article mentioned above presents research on the types of DNA sequences that can induce inversion events. Inversion breakpoints tend to have sequences with high identity located at the pairs of breakpoints. Those high identity sequences may pair up and illegitimately recombine, inducing an inversion event. The authors refer to this as nonallelic homologous recombination (NAHR), which screams out “HEY EVERYBODY, I’M A MOLECULAR BIOLOGIST UNFAMILIAR WITH THE PROPER DEFINITION OF HOMOLOGY!” It’s really just non-allelic recombination — there is no need and no justification to refer to homology.

The publication heavily cites the recent literature on segmental duplications and inversions in the human genome, of which there is quite a lot. But there is not a single citation to any Drosophila research. It’s hard to imagine that, in a paper dealing with repeat induced rearrangements in a eukaryotic genome, the authors fail to cite anything by Bill Engels (here would be a good place to start). Do the authors not know about the Drosophila literature? Do they not care to know? Do they take the attitude that if it’s done in humans it’s more important, and, therefore, there is no need to cite the previous research which discovered similar things in non-human systems?

Additionally, this brings up the broader question of the use of model organisms in genomics. Prior to the human genome project, non-human systems were quite useful for studying phenomena that could not be examined in humans. This is still the case in many other biological subdisciplines where analyzing mutants, studying many nearly identical individuals, or sacrificing organisms is required. But genomics relies only on DNA sequences, which can be obtained from any organism. And, as it currently stands, human sequence data are among the best for doing genomics, in terms of the quality of the sequence, the freely available polymorphism data, and the sequences available from closely related taxa.

What use are model organisms if we can do the same analyses in humans? First off, this question assumes that the purpose of studying non-human models is so that we can better understand humans. That’s not necessarily the case, as many non-human studies are for the purpose of increasing our understanding of all biology. Not all of the life sciences are dedicated towards improving the well being of some arrogant biped. Furthermore, a lot science is about finding generalities that apply broadly to many different systems. Studying diverse models allow us to identify commonalities shared by many taxa, as well as differences between those taxa.

With that in mind, we must redefine what it means to be a model organism for the purpose of genomics. These are not models of human biology and disease. These are models of all life. We should sample organisms from various diverse taxa to determine what genomic features that have in common, how they differ, and how these features evolve. And that’s another thing missing from the article discussed above — implications for evolution. To compare, here is the most recent article I’ve come across on chromosomal rearrangements in Drosophila. I’m a bit biased, but I like the Drosophila article much better.

Comments

  1. #1 Neil
    April 11, 2007

    I seem to recall that when last year’s Nobel was awarded for the discovery of RNA interference, there was a strong feeling that the plant scientists missed out – it wasn’t taken seriously until the worm guys got their hands on it.

    Totally agree with you about so-called model organisms: they’re models for biology, not just humans. And in this age of genomics, there’s no reason that a “lowly” archaeon can’t give you insight into a human.

  2. #2 Laurent
    April 11, 2007

    Where did you get this feeling about plant biologists?

  3. #3 p-ter
    April 11, 2007

    The authors refer to this as nonallelic homologous recombination (NAHR), which screams out “HEY EVERYBODY, I’M A MOLECULAR BIOLOGIST UNFAMILIAR WITH THE PROPER DEFINITION OF HOMOLOGY!” It’s really just non-allelic recombination — there is no need and no justification to refer to homology.

    whatevs, we human geneticists call it non-allelic homologous recombination and I’ll defend it. the sequences mediating the crossing-over are homologous– they’re descended from a single ancestral copy (having reproduced via transposons or recent segmental duplications).”Non-allelic recombination” doesn’t take into account, well, the homology between the sequences. you got a problem wit dat? :)

    also, PNAS has pretty strict length rules and the authors’ focus is medicine; it’s natural that they cite human studies. there’s room for pure biology and medicine in genomics; some people choose to focus more on one or the other. so it goes.

  4. #4 RPM
    April 11, 2007

    Where did you get this feeling about plant biologists?

    From plant biologists. They have an inferiority complex. Kind of like biologists who work on non-human systems.

  5. #5 p-ter
    April 11, 2007

    it wasn’t taken seriously until the worm guys got their hands on it.

    well, it wasn’t taken seriously until the worm guys got their hands on it and figured out what was going on. that was pretty much the key…

    see the letter to Science from Rich Jorgensen(the guy who studied RNAi in plants)?:

    In Jennifer Couzin’s recent piece on the Nobel Prize that was awarded to Andy Fire and Craig Mello, an anonymous RNA interference (RNAi) researcher was quoted as saying “plants got screwed” (“Method to silence genes earns loud praise,” News of the Week, 6 Oct., p. 34). As an early participant in the plant RNA silencing field, I take exception with this view. I feel that the Nobel committee’s decision to focus on the central role of double-stranded RNA (dsRNA) was quite appropriate; it was this specific discovery that broke an obscure field wide open and brought it to the attention of all biologists. The publication of RNAi (1) catalyzed new interactions between plant and animal geneticists that led directly to all kinds of discoveries about the mechanisms underlying and related to RNAi. The impact on biological research from understanding that dsRNA is a key intermediate in triggering RNAi has been huge. dsRNA is used as a tool to silence genes in a significant percentage of all papers on eucaryotic biology (for instance, “RNA interference” was mentioned in more than 20% of all research articles published this year in the journal I edit, The Plant Cell, the leading primary research journal in plant biology). Of course, there were also many other very important discoveries in the RNAi field, by researchers working in plants, animals, and fungi, but none of them had the same catalytic impact on biology as did Fire and Mello’s key insight and elegant experimentation. The Nobel committee decided to keep the award simple and straightforward for good reason.

    The Nobel Prize is not really about making scientists famous–it is about making science interesting and accessible to the public. RNAi is a wonderful vehicle for communicating the importance and potential of basic research. Many more people will now understand the value of fundamental research because of the RNAi story, and that is fantastic news for all scientists.

    Congratulations, Andy and Craig, and thank you for your tremendous contribution to science!

    Rich Jorgensen
    Editor in Chief
    The Plant Cell
    Department of Plant Sciences
    University of Arizona
    Tucson, AZ 85721-0036, USA

  6. #6 RPM
    April 11, 2007

    p-ter – the homology is due to high sequence identity, not common ancestry. It’s the molecular biologist’s definition of homology, not the evolutionary biologists. That wasn’t a swing at human biologists; it was a swing at molecular biologists. Sure, those high identities are often due to common ancestry, but it’s not a necessary requirement.

    As for neglecting relevent literature because of length requirements — they managed to cite a shitload of papers on human segmental duplications and rearrangements. Certainly one of those references could have gone to a classic paper on repeats inducing rearrangements in Drosophila. Not doing so makes it seem like you don’t understand what the hell you’re writing about.

  7. #7 Tex
    April 11, 2007

    As a plant molecular biologist, I would like to make two points:

    1) Just because some is a molecular biologist, that does not give them the right to completely ignore well-established usage of valuable terms such as ‘homology.’ If you want to use an impressive word to mean ‘Geez, these two sequences sure look alike,’ then make up one, and leave homology alone. Same thing goes for ‘synteny,’ another perfectly good word derived from cytogenetics that has been completely bastardized by many well-meaning, but narrowly educated, molecular biologists.

    2) I believe part of the disappointment in the plant community over the Nobel Prize for RNAi was not so much the oversight of Rich Jorgensen and other pioneers in the field, but the oversight of David Baulcombe, whose lab first demonstrated the existance of small RNAs involved in the process. See this seminal paper: A. Hamilton and D. Baulcombe. Science. 1999 Oct 29;286(5441):950-2.

  8. #8 p-ter
    April 12, 2007

    Certainly one of those references could have gone to a classic paper on repeats inducing rearrangements in Drosophila. Not doing so makes it seem like you don’t understand what the hell you’re writing about.

    but why would is make it seem like they don’t know what the hell they’re talking about? Let’s assume they haven’t read the literature on drosophila– still, they’ve read the relevant human papers, which should give enough information to know that inversions are important medically (all they really care about for this paper). maybe they’re unaware of the evolutionary relevance of anything their doing, but they still know what they’re doing from a medical point of view.

    I’ve written papers where reviewers make me put more references into certain parts, and it always seems kind of silly– I appreciate knowing about the papers, but they had no impact on what I did (except partially through papers I read that were influenced by those previous papers, or something). or maybe my philosophy towards citations is off– should they really be a “shout out” to people who work in similar areas as you?

  9. #9 p-ter
    April 12, 2007

    the oversight of David Baulcombe, whose lab first demonstrated the existance of small RNAs involved in the process. See this seminal paper: A. Hamilton and D. Baulcombe. Science. 1999 Oct 29;286(5441):950-2.

    ah, ok. thanks for clearing that up.

  10. #10 Reed A. Cartwright
    April 12, 2007

    Wait, did they mean “non-homologous recombination”?

  11. #11 RPM
    April 12, 2007

    p-ter, it’s not the medical relevance of inversions that the drosophila literature is good for, and I wouldn’t feel totally bummed in they failed to include anything on the evolutionary importance of inversions in drosophila (although they do cite papers from the human literature that deal with rearrangements and evolution). But to discuss repeat induced rearrangements and give not a single reference to anything by Bill Engels suggest to me a poor understanding of the field.

  12. #12 Uschi Symmons
    April 12, 2007

    Thanks loads for this short briefing, I really liked it, especially since I somehow ended up the road of human genomic rearrangements in my studies and I found it extremely difficult to get the “bigger picture”: There’s such a wealth of papers on human genetics and rearrangements, that once you bury yourself in those you never get round to model organisms at all. However, as to NAHR – as far as I understood it, homologous in the expression often refers to duplicated sequences, which in this case are homologs (paralogs to be more precise) since they have common ancestry, thus it is correct to call it NAHR. I don’t know yet in what context this comes up in the paper (I’m getting round to that :), so I might have to revise this thought… Also, reviews I have read (eg. Bailey and Eichler: Primate segmental duplications, Nat Rev Genet, 2006) have highlighted that mammalian genomes differ from Drosophila and C.elegans because the carry more and much larger segmental duplications, and I believe this might contribute to why mammals/human are treated as special. Any thoughts on that?

  13. #13 RPM
    April 12, 2007

    Mammalian genomes differ from Drosophila genomes which differ from C elegans. But there are similarities that can be useful to understand common processes shared amongst all species. Mammals tend to have large segmental duplications, and the duplications appear to induce rearrangements. Whereas in the drosophila, it’s transposable elements and other highly repetitive sequences that induce rearrangements. While some of the fine scale processes may differ in how duplications arise in these genomes, the molecular biology behind inversions appears to be quite similar.

    I am tentative to refer to non-allelic recombination as “homologous” because it’s not the homology that causes illegitimate recombination, it’s the high sequence identity between non-allelic sequences.

  14. #14 Laurent
    April 13, 2007

    Well, in this case… I remember having such feeling a long time ago, long before graduating. But that’s mostly because people didn’t even know that plants existed (can anybody really be blamed for this anyway?).

    My feeling is also that it may happen between highly reductionistic and more euristic biology. In this case just as much as in the previous one, that’s also only reflecting the modern state of biology after all. With a lot of people even not knowing there’s a very special state called an organism for example. And that sometimes, asking why on earth there would be organisms is a really interesting question that’s not that obvious…

    But as far as I can tell, I never had this feeling back when actually doing the science. So I wonder if this might not be something very localized.