The Genome Folding Problem

How long is the DNA strand of a human genome if you stretch it linearly? What are the contemporary methods used for investigating the structure of chromosomes? Professor of Health Sciences and Technology and Physics at Massachusetts Institute of Technology Leonid Mirny explains how polymer physics helps to solve biological problems.

We are trying to understand how the genome is folded in 3D, it’s actual spatial structure, and we’re also trying to understand what are the functional implications of this folding. Genome is not a homogeneous thing, there are genes, the regions where there are no genes, and we are trying to see what’s the functional role of this three-dimensional folding of the genome. This folding of the genome is not static. As cells divide they compactify their genome into dense chromosomes in metaphase and then separate the chromosomes. So genome is opening up after cell division and then closing for cell division.

When I isolate chromosomes and I chop them, I can now through a series of clever biochemical steps connect them into a single molecule. These two pieces that are far [from each other] on the linear chromosome are now going to be connected because they’re kept together by the glue. And after I connect them I can actually identify their nucleotide sequence. Through sequencing technology I can actually read DNA here and read the DNA sequence there. If I do it massively and in parallel I will get billions of such short reads, and each read tells me the nucleotide sequence of one piece of the hybrid and the other piece.

We are making first steps towards understanding this structure and solving this structure, so what we understood so far is that it’s not going to be a solid structure, like the structure of proteins, because these molecules are very long and flexible, these are going to be an ensemble of structures rather than a single structure. And in this ensemble chromosomes will have very different shapes, but nevertheless we’re trying to understand what are the principles of folding of this ensemble. So what forces drive folding of chromosomes, what organizational principles drive their further folding when they are folding into metaphase chromosomes and then segregation of chromosomes.