Field of Science

10,000 genomes – why?

In the genomics world that I inhabit, a consortium has just published an intriguing proposal to sequence the genomes of 10,000 vertebrate species. It’s described an article in the current Journal of Heredity – unusual in that this is not a research article, but a proposal. Nonetheless, the article is full of interesting facts about what we know (and don’t know) about vertebrate species and how they’re all related. It makes a good read for anyone interested in evolution; for example, how many people know that all vertebrates have a common ancestor who lived about 500-600 million years ago? Perhaps more interesting, evidence is emerging that we all share about 10,000 genes – which means that these 10,000 genes are so useful that their functions have been preserved for 500 million years.

The consortium is led by a number of outstanding scientists, including UCSC’s David Haussler and NIH’s Stephen O’Brien, both of whose work I like and have followed for years. And some aspects of this proposal are terrific: for example, they want to start collecting DNA now from 16,203 vertebrate species. This will make a great specimen collection for future work. (Heck, maybe I’ll even sign on to the project myself.)

But this proposal is more than that: it is also the opening salvo in an effort to raise $50-100 million for the sequencing of these species. The paper was announced with press releases and news articles in both Science and Nature, demonstrating that it is clearly a lobbying effort for new funding. Fair enough – science takes funding, and sometimes you have to build support for new ideas. However, given that two of the three leaders of the consortium are primarily funded by NIH, I can only guess at who they’re expecting to cough up the money. The NIH's human genome funding has been led by NHGRI, which continues to look for new ways to justify maintaining the size of its three enormous sequencing centers (the Broad Institute, Washington University in St. Louis, and Baylor College of Medicine). Now, let me say here that genomes are the bread and butter of my own work, and these centers have done terrific work for the past 10-15 years - and I've often collaborated with them. And I hope they will continue. But it hasn’t escaped my attention that the new NIH Director, Francis Collins, was a key force in building up those centers while he was Director of NHGRI, and we all know that the centers are near and dear to him.

But wait a minute: 10,000 genomes, none of which are human? Exciting idea, sure, but not for NIH. The NIH-led centers are already participating in the 1000 Genomes project, which is attempting to sequence 1000 individuals (at a low-level “draft” quality). If NIH wants to scale up, there are 6 billion more of us available. Admittedly, not everyone wants to have his/her genome sequenced, but plenty of us would be happy to volunteer. Take a look at the Personal Genome Project, which was started by George Church at Harvard, and is trying to sign up 100,000 humans to have their genomes sequenced.

So I’m going to be the skeptic here: if NIH is thinking of throwing its sequencing dollars at 10,000 more genomes, I suggest that it focus on humans rather than a broad collection of other vertebrates. (I know, this should be obvious, right? But sometimes NIH gets distracted.) We still have only scratched the surface of what there is to know about the human genome, and there’s plenty of DNA sequencing to do in the human population. The 10,000 genomes project sounds like a great mission for the National Science Foundation, which has ceded much of large-scale sequencing work to the NIH in the past 10 years, except for plant genomes and some bacteria. In fact, maybe this is a chance for NSF to have its own large-scale sequencing center – I’d be all for that. But I’m not at all convinced that NIH should spend its biomedical research dollars on 10,000 vertebrates. Let’s see how this plays out.

11 comments:

  1. It's true that I'm hard pressed to think of what we've learned from vertebrate sequences other than human.

    Oh, wait... lots of things! Ultraconservation, functional variation in genes, evolution of regulatory elements, evolution of repeats, and evolution of evolution (changes in the way isochores come about, for example). And those are just the things I've read about or worked on myself; I'm sure there's more.

    I think the search for understanding -- even health-related understanding -- has to have a wider focus than just human. Opening up genome sequencing to more systems, including new model systems and systems in which behavior and social groups are studied, just makes sense to me.

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  2. Of course we've learned from vertebrate sequences. But you don't know what we would have learned had we used, say, one tenth of the millions (billions?) spent by the large sequencing centers on something other than sequencing genomes. I've heard many biologist complain about exaclty the same thing, but only privately. Maybe Steven's post will help generate more public discussion.

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  3. I actually agree with that sentiment -- NIH seems to have followed a "sequence first, ask questions later" policy (which has redounded to my personal career benefit, but still sits poorly!)

    However, Steven suggests that we throw the money at human sequencing, rather than at vertebrate sequencing. If that's the choice, I'll take 10k vertebrates.

    I think a judicious mix would be best. With next-gen sequencing and especially large-insert paired-end sequencing, we can do a lot of good stuff to human genomes for very little money. Let's get some more non-human vertebrate genomes in there, too, while we're at it.

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  4. I was wondering why only vertebrates -- why leave behind the vast desert among the other >99% of life? We're only beginning to scratch the surface of bacterial and non-metazoan eukaryotic biodiversity, we're only beginning to uncover some truly amazing phenomena there. In the whole grand scheme of things, vertebrates are rather boring and insignificant... (not to mentioned, overstudied compared to everything else out there...)

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  5. Psi: good question. I think the answer is political rather than scientific - if my guess is correct, and they want to lobby NIH for funding, then it's easier to make the case that vertebrates are relevant to human health. And NIH already has launched the Human Microbiome project to study microbes on the human body. But from an evolutionary perspective, I agree with you.

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  6. Since it is only starting to get organized, I think it is not clear where the 10K Genomes Project will end up nor how much it will cost nor how it will be funded. Moreover, that's probably not critical at this early juncture, which is described in the paper. Genome-scale projects tend to be more like voyages of discovery, like Magellan, than hypothesis-driven studies. In a video interview (http://www.genome.gov/highlightPassthru.cfm?link=/multimedia/flash/videoPlayer2.cfm?videoID=10K_Genomes_Project), NHGRI Scientific Director Eric Green MD PhD, who is a co-author of the paper, and NHGRI Large-Scale Program Director Adam Felsenfeld, PhD, describe their individual views of the scientific promise of this effort. Dr. Felsenfeld predicts that it will not be centered in the large sequencing centers, but rather will likely be more distributed, which increases the need for organization. Getting the community interested in these results clearly will take consensus building and converstion, which this journal article has started.

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  7. I think this thread is wandering away from the real point. We want to know how genomes work. Sequencing them is a prologue to that enterprise. And genome/sequence comparisons have been a mainstay of functional studies. Genome comparisons are based on the assumption that a conserved stretch of sequence between genomes has a function or the forces of genetic drift and natural selection would sweep it away. So this evolutionary conservation is a useful tool and some say that function and evolution are so intertwined that we must understand both to understand function. In that case, a very deep dataset for comparison might provide a more sensitive metric that any we’ve had so far. (Andy Cameron at CCRG)

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  8. So I’m going to be the skeptic here: if NIH is thinking of throwing its sequencing dollars at 10,000 more genomes, I suggest that it focus on humans rather than a broad collection of other vertebrates. (I know, this should be obvious, right? But sometimes NIH gets distracted.)

    But I’m not at all convinced that NIH should spend its biomedical research dollars on 10,000 vertebrates.

    Well, no, it's not obvious. I'm not sure that's a very convincing argument for two reasons. First, $100 M represents < 0.5% of the annual budget for NIH. If this is a multi-year project and it really does cost less than $100 M, then it really is a drop in the bucket. Next, are you so sure that going from 1,000 to 11,000 human genomes would yield as much (even biomedically) as going from < 100 to 10,000 vertebrates?

    Rafa said:
    But you don't know what we would have learned had we used, say, one tenth of the millions (billions?) spent by the large sequencing centers on something other than sequencing genomes. I've heard many biologist complain about exaclty the same thing, but only privately. Maybe Steven's post will help generate more public discussion.

    And regarding the "waste" of money arguments, NHGRI's annual budget is on the order of $0.5 B. Of NIH's ~$30 B budget, cancer alone is $6 B. If you can make a forceful argument of ripping that money away from sequencing and applying it to a truly neglected area instead of the already well-funded research areas, I'm all ears. But to be honest, if you took ALL of NHGRI's budget and gave it to cancer research in NIH, do you think that spending $6.5 B instead of a paltry $6 B would substantially improve the pace of research?

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  9. JJE: There ought to be a word for this kind of political budget argument - we hear it all the time in Washington, D.C., and it goes just like yours: "X is only a small percent of the agency's budget, so it's surely worth investing that much blah blah blah."

    This argument is fatally flawed, though, because you can make similar arguments for hundreds of items, and quickly use up the entire NIH budget. And it's further flawed because that's not how NIH budget decisions are made. $100M in funding is a big chunk of precious biomedical research dollars, and putting it all in one "big" project is, in my view, highly questionable for a project that is not biomedical (let's be honest).

    Now, if you can convince the gov't to take $100M out of the Defense budget - where it really is a very, very tiny drop in the bucket - and spend that on sequencing, I'm all for it. We could simply cut one of the many earmarks that Congress attaches that DoD doesn't even want. But alas, that's not how the budget decisions are made either.

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  10. I was about to complain about the discrimination against basic science (personally, I've got beef with biomed...), but then I realised NIH, not NSF. So in that case, there definitely is something to your argument.

    Although I resent the implicit sentiment that basic science is 'not precious' compared to biomed. Medicine would be nowhere without basic science. And understanding systems besides humans is vital for progress even in human biology; for one thing, some organisms are just way better for certain studies than others. Good example: discovery of telomeres in ciliates -- it is because of their utterly surreal molecular genetics (two different nuclei, one of which is basically a bag of short eukaryotic plasmids...with telomeres) that the discovery of telomeres and telomerase happened much earlier than it probably would have without them. And telomeres happen to have medical importance, as an aside.

    I just get annoyed at hyped up fields ousting good basic science, without which those very popular fields become stagnant and unproductive. One can often sense intense elitism coming from the general direction of biomed, and it gets quite annoying... [/rant]

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  11. Don't get me wrong - I love basic science, and if I could I'd vastly increase the NSF budget. And NIH does tons of very basic science already, which I support. And by the way, I was a co-author on the Tetrahymena genome paper, so I'm a fan of studying ciliates too!

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