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.