By Brandon Keim October 8, 2009 | 3:16 pm | Categories: Biology, Genetics
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.”
As depicted in basic biology textbooks and the public imagination, the human genome is packaged in bundles of DNA and protein on 23 chromosomes, arrayed in a neatly X-shaped form inside each cell nucleus. But that’s only true during the fleeting few moments when cells are poised to divide. The rest of the time, those chromosomes exist in a dense and ever-shifting clump. Of course their constituent DNA strings are clumped, too: If the genome could be laid out end-to-end, it’d be six feet long.
For decades, some cell biologists suspected that the genome’s compression wasn’t just an efficient storage mechanism, but linked to the very function and interaction of its genes. But this wasn’t easy to study: Sequencing the genome destroys its shape, and electron microscopes can barely penetrate its active surface. Though its constituent parts are known, the genome’s true shape has been a mystery.
In April, a paper published in the Proceedings of the National Academy of Sciences linked patterns of gene activation to their physical proximity on chromosomes. It still provided the most persuasive evidence to date that genome shape matters, even though the researchers’ chromosome map was relatively low-resolution. The topography described in the latest research, published Thursday in Science, is far more detailed.
“It’s going to change the way that people study chromosomes. It will open up the black box. We didn’t know the internal organization. Now we can look at it in high resolution, try to link that structure to the activity of genes, and see how that structure changes in cells and over time,” said Dekker.
To determine genome structure without being able to directly see it, the researchers first soaked cell nuclei in formaldehyde, which interacts with DNA like glue. The formaldehyde stuck together genes that are distant from each other in linear genomic sequences, but adjacent to each other in actual three-dimensional genomic space.
The researchers then added a chemical that dissolved the gene-by-gene linear sequence bonds, but left the formaldehyde links intact. The result was a pool of paired genes, something like a frozen ball of noodles that had been sliced into a million fragmentary layers and mixed.
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.
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