The Shape of the Genome

The more we learn about the cell, the more and more sophisticated is becomes.  In biochemistry and molecular biology, it has long been known that shape is a crucial feature of macromolecules such as proteins and RNA – the functional, phenotypic core of the cell.  Change the shape of any particular protein or RNA and you are likely to change the function.  But it is now time to take that insight to a new level.

When it comes to the genome, we have long focused on it in linear terms – a mere sequence of nucleotides.  But thanks to some fascinating research, it is now becoming clear that we need to start thinking about the shape of the genome:

By breaking the human genome into millions of pieces and reverse-engineering their arrangement, researchers have produced the highest-resolution picture ever of the genome’s three-dimensional structure.

The picture is one of mind-blowing fractal glory, and the technique could help scientists investigate how the very shape of the genome, and not just its DNA content, affects human development and disease.

“It’s become clear that the spatial organization of chromosomes is critical for regulating the genome,” said study co-author Job Dekker, a molecular biologist at the University of Massachusetts Medical School. “This opens up new aspects of gene regulation that weren’t open to investigation before. It’s going to lead to a lot of new questions.”

[…]

By studying the pairs, the researchers could tell which genes had been near each other in the original genome. With the aid of software that cross-referenced the gene pairs with their known sequences on the genome, they assembled a digital sculpture of the genome. And what a marvelous sculpture it is.

“There’s no knots. It’s totally unentangled. It’s like an incredibly dense noodle ball, but you can pull out some of the noodles and put them back in, without disturbing the structure at all,” said Harvard University computational biologist Erez Lieberman-Aiden, also a study co-author.

In mathematical terms, the pieces of the genome are folded into something similar to a Hilbert curve, one of a family of shapes that can fill a two-dimensional space without ever overlapping — and then do the same trick in three dimensions.

How evolution arrived at this solution to the challenge of genome storage is unknown. It might be an intrinsic property of chromatin, the DNA-and-protein mix from which chromosomes are made. But whatever the origin, it’s more than mathematically elegant. The researchers also found that chromosomes have two regions, one for active genes and another for inactive genes, and the unentangled curvatures allow genes to be moved easily between them.

Lieberman-Aiden likened the configuration to the compressed rows of mechanized bookshelves found in large libraries. “They’re like stacks, side-by-side and on top of each other, with no space between them. And when the genome wants to use a bunch of genes, it opens up the stack. But not only does it open the stack, it moves it to a new section of the library,” he said.

Let me take this new knowledge and use it to propose a hypothesis that might explain a current anomaly.  The proteins that package the DNA are known as histones and histones are among the most highly conserved proteins in eukaryotes.  Yet many years ago, Michael Behe did some research that showed several of the highly conserved amino acids can be replaced in yeast without any detectable negative effect.

More recently, scientists have discovered non-coding DNA that is also very highly conserved, but when you remove it from the genome, nothing seems to be wrong.

These anomalies are currently explained by arguing that survival in a lab setting cannot be extrapolated to survival in the wild.  That is, while such mutated lab mice or yeast might be able to survive just fine in the controlled and comfortable lab environment, out in the wild, there are likely to be some conditions that would put these mutated creatures at a distinct disadvantage.

While this explanation rings true, it doesn’t tell us how this happens.  It doesn’t provide the possible mechanism.  But now we have one.  To see it, consider a commonly isolated mutant in the lab – a temperature sensitive mutant.  To get such a mutant, scientists randomly mutate protein sequence and then select for mutants under elevated temperatures.  As it turns out, many proteins can acquire mutations without any negative effect if kept at lower temperatures, but become non-functional if shifted to higher temperature.  The thinking is that the protein structure has been weakened, but can remain intact at lower temps.  Only when shifted to the higher temperature does the network of crucial chemical bonds break down.

So here is my hypothesis.  We can propose that various environmental stresses have the potential to challenge the shape of a particular genome.  We can thus extrapolate and propose that mutations in the highly conserved histone and non-coding DNA sequence are analogous to temperature sensitive mutants – they weaken the structural integrity of the genome and environmental stresses perturb genomic structure and with it,  the regulatory networks.  The weakened system collapses.

Regardless of the truth of this hypothesis, it would seem clear that the organizational shape of a genome is something we will have to consider when assessing non-coding (“junk”) DNA, along with its re-formatting during evolution.

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12 responses to “The Shape of the Genome

  1. Gorebloodgore

    I am shocked there hasn’t been many comments on your blog lately? Ill admit I have been lazy lately. I have some catching up to do haha.

  2. Discussions about Alu domains, SRP9/14 proteins, and elongation arrest, aren’t exactly the type of talk to get a lot of people talking. 🙂

    I suppose I could always do a Richard Dawkins post. :p

  3. Yeah in fact im surprised you don’t have 10 comments from the word dawkins alone haha. Maybe try writing with a british accent haha. Ill be honest with you though, I haven’t been reading much of this stuff lately because its october, im reading nerdy horror novels!

  4. I should ban you for that!!

    Just kidding.

    Hey, if you have any good horror novel recommendations, just pass them my way. Can’t say I’ll read them anytime soon, but it would be good to have a list handy.

  5. Here’s another news account about this:

    http://news.bbc.co.uk/2/hi/science/nature/8296861.stm

  6. Ok, I have a bunch of things to say haha. First of all I am just now finally reading this blog even though I have posted two comments haha.

    Next you said “These anomalies are currently explained by arguing that survival in a lab setting cannot be extrapolated to survival in the wild. That is, while such mutated lab mice or yeast might be able to survive just fine in the controlled and comfortable lab environment, out in the wild, there are likely to be some conditions that would put these mutated creatures at a distinct disadvantage.”

    I was just wondering if this was something that had real scientific backing. Because to me that just doesnt sound right “ok, well you guys in the lab proved what happens in a lab setting… but the real test is what happens outside…. but were not doing that” Or am I wrong and there is outside information?

    Finally to be honest, I’m just not sure I completly follow you. I am confused on how your hypothesis fits with the first part of your post about the genome. Are you saying that the weakend system collapses because the genome compensates and changes its shape?

    Anyhow, about the books. I stongly recommend reading “The Hellbound Heart” By Clive Barker. It is what “Hellraiser” was based off. Its a short story and takes about as much time to watch the movie. Thats probably my favorite horror book. Its really hard to find good ones, im constantly dissapointed. I am now reading a promising vampire novel called 13 Bullets. Really creative and orriginal as well as action packed. Here is a funny trailer for it http://www.youtube.com/watch?v=PSFFYIg3vAI

    Let me know if you know of any horror novels 🙂

  7. I was just wondering if this was something that had real scientific backing.

    The authors of the paper, for example in the case of mice, offered this as an alternative explanation:

    “Accordingly, our results were unexpected. It is possible that our assays were not able to detect dramatic phenotypes that under a different setting, for instance, outside the controlled laboratory setting, would become evident. Moreover, possible phenotypes might become evident only on a longer timescale, such as longer generation time.”

    (2007) Deletion of Ultraconserved Elements Yields Viable Mice. PLoS Biol 5(9): e234. doi:10.1371/journal.pbio.0050234

    I myself am not aware of any evidence but I strongly suspect that would probably be the case.

    Very interesting hypothesis being offered as possible mechanism as to why.

  8. Form leads function..function needs aim..aim needs a pathway to organize called organization, this needs design and design needs the designer/designers at the end..in the matrix of life..this is the razor of intelligence unless you are condemmed by materialism.

  9. Gore,

    I was just wondering if this was something that had real scientific backing. Because to me that just doesnt sound right “ok, well you guys in the lab proved what happens in a lab setting… but the real test is what happens outside…. but were not doing that” Or am I wrong and there is outside information?

    Think of a zebra in the zoo vs. a zebra in the wild. The zebra in the wild is likely to experience many stresses not ever experienced by the zoo zebra – going without food for a long time, going without water for a long time, being injured, being hunted by a predator, being infected with various parasites, etc.

    It’s the classic problem of lab biology vs. field biology. The former allows for much more controlled experiments, but then extrapolation to the real world becomes questionable. The latter gets you closer to reality, but then you have a very hard time controlling all the variables and get more questionable data.

  10. Pingback: Alu Mania «

  11. Pingback: The SRP, Alu Elements, and Nudging «

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