Genetic origami

Here’s another piece from BBC Future. Again, for non-UK readers the final version is here.
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What shape is your genome? It sounds like an odd question, for what has shape got to do with genes? And therein lies the problem. Popular discourse in this age of genetics, when the option of having your own genome sequenced seems just round the corner, has focused relentlessly on the image of information imprinted into DNA as a linear, four-letter code of chemical building blocks. Just as no one thinks about how the data in your computer is physically arranged in its microchips, so our view of genetics is largely blind to the way the DNA strands that hold our genes are folded up.

But here’s an instance where an older analogy with computers might serve us better. In the days when data was stored on magnetic tape, you had to worry about whether the tape could actually be fed over the read-out head: if it got tangled, you couldn’t get at the information.

In living cells, DNA certainly is tangled – otherwise the genome couldn’t be crammed inside. In humans and other higher organisms, from insects to elephants, the genetic material is packaged up in several chromosomes.

The issue isn’t, however, simply whether or not this folding leaves genes accessible for reading. For the fact is that there is a kind of information encoded in the packaging itself. Because genes can be effectively switched off by tucking them away, cells have evolved highly sophisticated molecular machinery for organizing and altering the shape of chromosomes. A cell’s behaviour is controlled by manipulations of this shape, as much as by what the genes themselves ‘say’. That’s clear from the fact that genetically identical cells in our body carry out completely different roles – some in the liver, some in the brain or skin.

The fact that these specialized cells can be returned to a non-specialized state that performs any function – as shown, for example, by the cloning of Dolly the sheep from a mammary cell – indicates that the genetic switching induced by shape changes and other modifications of our chromosomes is at least partly reversible. The medical potential of getting cells to re-commit to new types of behaviour – in cloning, stem-cell therapies and tissue engineering – is one of the prime reasons why it’s important to understand the principles behind the organization of folding and shape in our chromosomes.

In shooting at that goal, Tom Sexton, Giacomo Cavalli and their colleagues at the Institute of Human Genetics in Montpellier, France, in collaboration with a team led by Amos Tanay of the Weizmann Institute of Science in Israel, have started by looking at the fruitfly genome. That’s because it is smaller and simpler than the human genome (but not too small or simple to be irrelevant to it), and also because the fly is genetically the best studied and understood of higher creatures. A new paper unveiling a three-dimensional map of the fly’s genome is therefore far from the arcane exercise it might seem – it’s a significant step in revealing how genes really work.

Scientists usually explore the shapes of molecules using techniques for taking microscopic snapshots: electron microscopes themselves, as well as crystallography, which considers how beams of X-rays, electrons or neutrons are reflected by molecules stacked into crystals. But these methods are hard or impossible to apply to molecular structures as complex as chromosomes. Sexton and colleagues use a different approach: a method that reveals which parts of a genome sit close together. This allows the entire map to be patched together piece by piece.

It’s no surprise that the results show the fruitfly genome to be carefully folded and organized, rather than just scrunched up any old how. But the findings put flesh on this skeletal picture. The chromosomes are organized on many levels, rather like a building or a city. There are ‘departments’ – clusters of genes – that do particular jobs, sharply demarcated from one another by boundaries somewhat equivalent to gates or stairwells, where ‘insulator’ proteins clinging to the DNA serve to separate one domain from the next. And inactive genes are often grouped together, like disused shops clustered in a run-down corner of town.

What’s more, the distinct physical domains tend to correspond with parts of the genome that are tagged with chemical ‘marker’ groups, which can modify the activity of genes, rather as if buildings in a particular district of a city all have yellow-painted doors. There’s evidently some benefit for the smooth running of the cell in having a physical arrangement that reflects and reinforces this chemical coding.

It will take a lot more work to figure out how this three-dimensional organization controls the activity of the genes. But the better we can get to grips with the rules, the more chance we will have of imposing our own plans on the genome – silencing or reawakening genes not, as in current genetic engineering, by cutting, pasting and editing the genetic text, but by using origami to hide or reveal it.

Reference: T. Sexton et al., Cell 148, 458-472 (2012); doi:10.1016/j.cell.2012.01.010