Wednesday, June 16, 2010

Richard Dawkins Talks About the Human Genome

 
Richard Dawkins is hosting a four part series on the human genome to be broadcast on BBC radio [The Age of the Genome]. Here's part of the summary for episode 1.
In spite of the advances, there have been some surprises and deepened mysteries. One of the greatest shocks was the finding that we have far fewer genes than scientists had assumed before they read out our genetic instructions. It takes no more genes to make a person than it does to make a simple microscopic worm. What makes a man different from a worm lies more in what researchers now calling the Dark Matter of the genome - 300 million letters of genetic code which work in currently mysterious ways.

Richard Dawkins is an evolutionary biologist at Oxford University and the author of numerous books on evolution and genetics such as 'The Selfish Gene'. In interviews with scientists who led the initial effort to decode the genome and those who are now at the forefront of genetic research, Richard brings his evolutionary insights and fascination with the universal genetic code of life to illuminate how far we've come, and where we are heading in the Age of the Genome.
Note to Richard,

Many scientists, including the experts in the subject, expected there to be about 30,000 genes in our genome. They were pretty close to being right. No surprises there.

What makes a man different from a worm is that we have a smallish number of different genes and the genes we have in common are regulated differently. This conclusion comes from studies in developmental biology that were completed before the Human Genome Project began. Differences in regulating gene expression can be easily accomplished by changing a few base pairs in the promoter/enhancer region of the gene. No mystery there. The field is called evolutionary developmental biology and it's based on an understanding of evolution.

The "dark matter" is junk. The sequence of the human genome goes a long way toward proving what was suspected back in 1970. That's not a surprise. It's a prediction confirmed. Everything we know about the evolution of genomes in diverse species is consistent with the idea that much of our genome has no function. Evolution explains pseudogenes, it explains the so-called C-value paradox, it explains transposons and selfish DNA, it explains highly repetitive sequences. The "dark matter" has been exposed to the light of day and it looks like junk.


12 comments:

  1. You may be right about early estimates of the gene count being in the right ballright, but you are wrong to dismiss "dark matter" as junk.

    The term is used in different senses by biologists but most commonly refers to whatever it is in the genome that explains our "missing heritability".

    It probably consists mainly of rare variants in protein-coding or regulatory DNA - but whatever it is, it isn't junk by definition in this sense of the term.

    Which is not to say that most of our DNA isn't junk, that's a completely different issue.

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  2. Michael Le Page says,

    You may be right about early estimates of the gene count being in the right ballright, but you are wrong to dismiss "dark matter" as junk.

    The term is used in different senses by biologists but most commonly refers to whatever it is in the genome that explains our "missing heritability".


    As you mentioned, the term "dark matter" has multiple meanings. Here's one [doi:10.1371/journal.pbio.1000370].

    It seems, in retrospect, that understanding the protein-coding portion of the genome was the easy part; it's the other 98% that's the real challenge. Once derided as mere “junk DNA”—the useless relics of ancient mistakes—the non-coding regions recently earned a great deal more respect, stemming from a series of reports that these regions were hotbeds of transcription. The abundance of RNA signals from this mysterious genomic “dark matter” appeared to indicate that the genome was up to a whole lot more than simply churning out proteins from well-described genes.

    I don't know what definition people are using unless they tell me. The onus is on them to state what they mean and not on me to guess.

    In my experience, the definition above is more common than any other I've come across.

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  3. The problem with the definition comes from that tendency for authors to dramatize their discoveries. Thus we see people talking about how "junk DNA" is not really junk because they discovered, say, some promoters that derived from transposons.

    Then people don't put that in its true perspective, the discovery does not mean all the huge amounts of DNA we have are promoters deriving from transposons. It is only a tiny little insignificant bit. A bit so incommensurable that it does not even make us change the proportion calculated to be junk. Given the need for drama, this is not even mentioned. Conclusion: no such thing as junk.

    I take it to be societal entropy. No way to stop it. It seems to be a natural tendency that the more complex we become in terms of science and scientific disciplines (thus specialization), the more the scholarship will erode.

    --Gabo

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  4. There are plenty of possible functions for all the "junk". It can be used in regulating genes. This idea is supported by the fact
    that most of the conserved DNA in the human genome is outside the
    exons. And there is lots of regulatory DNA that is not conserved. There are examples in which regulatory sites are found in repeats etc. It can be important for the structure of the genome. There have been a series of recent papers on the 3d organization/conformations of genomes. And also on nucleosome packaging and higher-order chromatin packaging. An interesting angle on thus idea is that the length of the DNA may be as important as it's sequence composition. It can serve as a "reservoir" of potentially functional elements. So part of the reason that complicated organisms tend to have large genomes is because they need the flexibility.

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  5. Anonymous says,

    There are plenty of possible functions for all the "junk". It can be used in regulating genes. This idea is supported by the fact
    that most of the conserved DNA in the human genome is outside the
    exons.


    There are many things wrong with this explanation.

    First, why should some species of onion need eight times as much "regulatory" DNA as others? Furthermore, there's no reason to suspect that humans need that much more "regulatory" DNA than nematodes or fruit flies. It's an idea that doesn't fit in with what we know about gene expression and development.

    Second, the amount of DNA couldn't possibly be significant in the debate about junk DNA. Therefore, it's almost always a red herring whenever someone raises the possibility of regulation. Perhaps you could tell us how much of our genome is devoted to regulation, according to this explanation?

    Third, the idea that most of the "conserved DNA" is outside of the exons doesn't stand up to close scrutiny. It depends very much on your definition of "conserved" and on the calculations of what you should expect from random mutation. (i.e., what's the amount expected if the DNA isn't under selective constraint).

    Having said that, there's no question that lots of DNA outside of exons is absolutely essential. Nobody denies that. Again, the question is about quantity. How much of our genome is "conserved" according to the best estimates that you've read?

    It can serve as a "reservoir" of potentially functional elements. So part of the reason that complicated organisms tend to have large genomes is because they need the flexibility.

    This is a possibility, provided our genomes were designed by an intelligent designer who could plan for the future. But it's a rather silly argument if you stick to real science.

    You you really believe that some species of onion are much better at planning for the future than others? Do you really believe that humans are better prepared for the future than bats? (Bats have a lot less DNA in their genomes.)

    This is an idea that needs to be squelched. Think about what the explanation is actually saying. It says that 90% of our genome is currently useless but we're under selection to keep it around because every million years or so it evolves into something useful.

    That's not consistent with modern evolutionary theory. Proponents of this explanation are challenging the very basis of our understanding of evolution. If that's what you want to do, then fine, go for it. But be sure you understand the implications.



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  6. @Gabo,

    Exactly right.

    Isn't "peer review" supposed to eliminate nonsense like that? Why isn't it working?

    If scholarship is eroding—and I agree that it is—then how is this happening? That's not how science is supposed to work.

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  7. Hi Larry,

    You posted other interesting stuff, so I feel a bit guilty of making you come back to this one. But yu make some good questions:

    Isn't "peer review" supposed to eliminate nonsense like that? Why isn't it working?

    Because it is all business today. "Peers" only semi-read the manuscripts. I could give you many examples from my experience submitting manuscripts and grants. Imagine, one of the worst ones. The reviewer said I did not mention how I would test some predictions. But one third of the application was exactly about that.

    If scholarship is eroding—and I agree that it is—then how is this happening? That's not how science is supposed to work.

    Agreed. I often find myself thinking of getting out of science. But somehow convince myself that maybe I can just accept this reality, and just keep my self-respect, and make my best to be a good scientist regardless of how things seem to be going.

    I think it is happening because of mass production. Because we have taken scholarship for granted. Example, we have not felt the need to tell students they should read load and loads of articles (I always felt they would know that, then got a few surprises) ... this is what I call entropy. We learned a lot by interacting with like-minded scientists, kind of "informally." Maybe we did not notice how important those lessons were, and thus, by generation, we forgot one detail or another. Then add numbers to the problem.

    Man, I don't want to get depressed. Finding your blog was a nice surprise anyway.

    Best,
    --Gabo

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  8. How much of our genome is "conserved" according to the best estimates that you've read?



    I think it's around 5 or 6% based on what I've read and heard. Here's one of the classic references. I don't think the numbers have changed much. This is all based on primary sequence alignments. Some people get higher numbers if you consider conservation of things like GC content and transformations of base content that may influence DNA or RNA structure, and/or if you allow for "shuffling" (i.e. local inversions and rearrangements), but those are harder to calibrate and there are more caveats in my view.



    Genome Res. 2005 Aug;15(8):1034-50. Epub 2005 Jul 15.
    Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes.
    Siepel A, Bejerano G, Pedersen JS, Hinrichs AS, Hou M, Rosenbloom K,
    Clawson H, Spieth J, Hillier LW, Richards S, Weinstock GM, Wilson RK, Gibbs RA, Kent WJ, Miller W, Haussler D.

    Abstract
    We have conducted a comprehensive search for conserved elements in
    vertebrate genomes, using genome-wide multiple alignments of five
    vertebrate species (human, mouse, rat, chicken, and Fugu rubripes).
    Parallel searches have been performed with multiple alignments of four insect species (three species of Drosophila and Anopheles gambiae), two species of Caenorhabditis, and seven species of Saccharomyces. Conserved
    elements were identified with a computer program called phastCons, which is based on a two-state phylogenetic hidden Markov model (phylo-HMM). PhastCons works by fitting a phylo-HMM to the data by maximum likelihood, subject to constraints designed to calibrate the model across species groups, and then predicting conserved elements based on this model. The predicted elements cover roughly 3%-8% of the human genome (depending on the details of the calibration procedure) and
    substantially higher fractions of the more compact Drosophila
    melanogaster (37%-53%), Caenorhabditis elegans (18%-37%), and Saccharaomyces cerevisiae (47%-68%) genomes. From yeasts to vertebrates, in order of increasing genome size and general biological complexity, increasing fractions of conserved bases are found to lie outside of the exons of known protein-coding genes. In all groups, the most highly conserved elements (HCEs), by log-odds score, are hundreds or thousands of bases long. These elements share certain properties with ultraconserved elements, but they tend to be longer and less perfectly conserved, and they overlap genes of somewhat different functional
    categories. In vertebrates, HCEs are associated with the 3' UTRs of
    regulatory genes, stable gene deserts, and megabase-sized regions rich in moderately conserved noncoding sequences. Noncoding HCEs also show strong statistical evidence of an enrichment for RNA secondary structure.

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  9. @ Anonymous,

    So, if 5% to 6% of our non-exon genome is "conserved" by some criteria then how does this affect the idea that 90% of our genome is junk?

    Isn't it pretty much irrelevant?

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  10. It's more of a proof of concept. There are also many examples of non-conserved regulatory sites.

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  11. @ Anonymous,

    What concept does it prove? That there are non-exon essential sequences? That's been known for half a century.

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  12. July 22, 2010

    Hallo Larry,

    You say

    "Evolution explains pseudogenes, it explains the so-called C-value paradox, it explains transposons and selfish DNA, it explains highly repetitive sequences. The "dark matter" has been exposed to the light of day and it looks like junk"

    That is all OK but it doesn't explain why there were 18366 or so genes in the first place. Or do you think it has been a matter of Creation?

    Numbers are an invention of humans*. Even without PCR etc. it is very easy to predict a final number of 18000 genes**. It suggests we don't know anything about the "Ding an Sich" (Kant).

    Jan Bijman

    *http://nl.wikipedia.org/wiki/Luitzen_Egbertus_Jan_Brouwer)
    **www.janbijman.eu/hotice.pdf

    ReplyDelete