Monday, October 26, 2009

The genome in three dimensions

We all learn about DNA as a string of letters, of A's, C's, G's, and Ts, so it's not surprising that we tend to think of DNA as linear. But, inside the cell, where it really matters, DNA is actually wound up into a three-dimensional ball. That this is so has been known for a long time, but little has been known about the organization of that structure. A paper in the Oct 9 Science (Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome, Lieberman-Aiden et al., p 289-293) discussed on the BBC website here, begins to correct this. (The figure to the left is from the paper, via the BBC.)

Using a series of clever molecular techniques to cut and sequence neighboring pieces of DNA, Lieberman-Aiden et al. generated a compendium of interacting bits of DNA. That is, for each part of the genome, they were able to determine its neighbors in three dimensional space. Among other things, they show that distant DNA sequences interact with and regulate each other in ways that aren't easily envisioned when we conceive of DNA as linear sequence alone. In addition, they determined 'contact probabilities' for parts of the genome as a function of genomic distance (number of basepairs away), finding that intrachromosomal contact probabilities are greater than those for interchromosomal contact. Further, interchromosomal contact is most likely between small gene-rich pairs of chromosomes.

The current study is, of course, following up on earlier results of similar investigations, but based on a more powerful molecular method. Conventional wisdom has been that DNA has to be tightly wound in order to fit in the cell -- unwound, it's 2 meters long, so it has be be compacted somehow to fit into the cell, never mind the nucleus of eukaryotic cells.

But DNA seems to be packaged in a very orderly way, and reflects whether or not genes in a particular spot are open for expression. The packaging seems to be replicable, if the new paper is correct. And, this brings to mind a number of questions including whether this explains why it has been so difficult to track down regulatory regions for many specific genes. Is the pattern of inter- and intra-chromosomal contact the result of functional constraints, specific sequence-based interactions, or natural selection? Or is it just how DNA winds itself up, given its overall structure? How sensitive is the cell to its packaging? If someone's DNA doesn't roll up right, are they selected against?

If selection is important, there must be many opportunities for--that is, need of--cooperation that enable the DNA to fold up and around itself, as Lieberman-Aiden et al. demonstrate; not only does winding of DNA into this tight ball fit it into the cell, but it also facilities contact between pieces of chromosomes, enabling cooperative interactions such as gene regulation. If there are functional reasons why these alignments occur, then there would be co-evolutionary constraints that maintain their compatibility--what we refer to in our book as cooperation.

As we emphasize in our writing, cooperation is a fundamental principle of life, and these results reinforce that view. We'll have more to say on this subject after Ken and a colleague give a seminar on the Lieberman-Aiden et al. paper.

-Anne and Ken

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