DNA, It Turns Out, Is A Lot More Loopy
ARUN RATH, HOST:
We may have mapped the human genome, but what we don't know about our own genetic code could fill libraries. For example, how do you fit a really long strand of DNA into a tiny cell nucleus?
SUHAS RAO: It's kind of equivalent to fitting a thread that's two football fields long into a head of a pin. You can't just randomly stuff it inside the nucleus.
RATH: That's Suhas Rao, a researcher at the Center for Genome Architecture at Baylor College of Medicine and Rice University. He says that DNA is looped and folded in an incredibly complex way and that the way the DNA is folded can determine which genes get turned on. That's why Rao and his colleagues have created a 3D, high-resolution map of those 10,000 tiny loops.
RAO: And these loops are bringing together far away sights along the DNA string and kind of organizing the genome.
RATH: So tell us about the importance of this 3D map that you've created. What sort of things are affected by where these loops fall?
RAO: Sure. So you have thousands of types of cells in your body, and they all have the same exact DNA inside them, but they all accomplish very different functions. And what we found is, actually, when we compared the maps of the 3D genome across different types of cells, we observed the kind of genomic origami. And so just like you can take a sheet of paper, and you can fold it up into a crane or a warrior depending on how - where you make the folds, a cell starts with the same genome. But depending on where these loops form, it can help the cell perform different functions, whether it becomes a lung cell or an immune cell or some other type of cell. So more and more, we're finding that folding drives function.
RATH: And another big discovery is that the protein that connects these loops tells which genes to turn on or off. Can you talk about the implications of that?
RAO: Yeah. So with diseases like, I mean, cancer and many other diseases, a lot of the variance or a lot of the mutations that affect those diseases affect proteins. They lie in regions that code for proteins in genes. But a lot of the variation actually lies in these hidden switches, these regions of the genome that turn genes on and off. But they don't actually code for anything. And so, after the human genome project, we've realized that these hidden switches are really important. But what we've realized is very difficult is connecting these hidden switches to which genes they turn on and off. And we can start to understand how mutations that we know are associated with disease, but we don't know why - we can start to understand, well, what are the pathways that are affected?
RATH: You're revealing some really major, important things that are determined by the shape of DNA. Now that you have this 3D map, are there other big things that we're going to discover about what's encoded in the shape of the DNA as well as the DNA itself?
RAO: I mean, I think we've gotten a much better sense now with these high-resolution 3D maps of the normal shape of the genome is. But in a lot of diseases, it's possible that the 3D structure changes dramatically, and the actual cause of the disease could be because you have a different kind of 3D shape of the genome. And so I think that's an important direction that we're kind of pursuing. Now that we understand how the genome is kind of folded in its normal way, we can start to kind of edit the shape of the genome. So we go beyond the normal genome editing that's happening now where we just edit the sequence, but we actually change the folds.
RATH: Suhas Rao is a researcher at the Center for Genome Architecture at Baylor College of Medicine and Rice University. Fascinating stuff - thanks very much.
RAO: Thank you for having me on.
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