There's more to life than sequences
The shape of DNA can play a crucial role in genetics, says Philip Ball.
Everyone knows what DNA looks like. Its double helix decorates countless articles on genetics, has been celebrated in sculpture and was even engraved on the Golden Record, our message to the cosmos on board the Voyager spacecraft.
The entwined strands are admired as much for their beauty as for the light they shed on the mechanism of inheritance. And geneticists have long regarded the sequence of its billions of constituent units as the 'book of life', with the implication that all the information needed to build an organism was held within this code.
But beauty has a tendency to inhibit critical thinking. DNA isn't simply a uniform double helix: it can be bent or kinked and may have a helical pitch of varying width, for example. These deviations from the 'perfect' double helix depend in subtle and complex ways on the particular sequence, so that two near-identical sequences can adopt quite different shapes.
And there is now increasing evidence that the molecular shape of DNA is not a delightful but incidental consequence of its function as a digital data bank. It is a crucial — and changeable — aspect of the way genomes work.
A new study in Science has now provided evidence that the precise shape of some genomic DNA has been determined by evolution1. In other words, genetics is not simply about sequence, but about structure too.
Part of biology's 'central dogma' is that in its sequence of the four fundamental building blocks (called nucleotide bases), DNA encodes corresponding sequences of amino acid units that are strung together to make a protein of precise shape and function. Yet as the human genome was laboriously unpicked, it became clear that about 98% of the DNA doesn't code for proteins at all.
It's not entirely clear what this DNA does, but it's clearly not all junk — the detritus of evolution, similar to obsolete files clogging up a computer. Much non-coding DNA has a role in cell function, since alterations in its nucleotide sequence can change the host organisms in noticeable ways. But we don't know how the non-coding DNA actually effects these changes.
This is the question that geneticist Elliott Margulies of the National Institutes of Health in Bethesda, Maryland and chemist Tom Tullius of Boston University, Massachusetts, set out to investigate.
Conventional wisdom says that the function of non-coding regions, whatever it is, should be determined by their sequence. But Margulies, Tullius and colleagues wondered if the shape of non-coding DNA might also be important.
The researchers hunted for similar-shaped sections of homologous non-coding DNA in 36 different species, and did a parallel comparison based on sequence data alone. Any strong matches across different species would imply that the sections of DNA have been preserved by evolution, and thus have an important biological function, they reasoned.
After the analysis, they found twice as many sections that matched up by shape than by sequence. So in these non-coding regions, the precise sequence of DNA nucleotides seems to be more important for the shape it confers on the DNA, rather than its intrinsic information content.
Although it doesn't explain exactly why shape matters, it certainly suggests that it is a crucial part of the story.
There are plenty of other good reasons to suspect that is true. For example, under particular conditions of saltiness or temperature, DNA can adopt radically different double-helical structures. It can also adopt triple- or quadruple-stranded forms, linked by different types of hydrogen-bonding between nucleotides. One of these bonding patterns is called Hoogsteen base-pairing.
Biochemist Naoki Sugimoto and colleagues at Konan University in Kobe, Japan, have recently used large polymer molecules in solution with DNA to mimic the crowded conditions of a real cell. They found that the Hoogsteen base-pairing forms of DNA became more stable in these conditions2,3,4.
Sugimoto thinks that this may be because the molecular crowding reduces the number of water molecules in the immediate vicinity of the DNA, something known to promote Hoogsteen pairing.
Mechanical effects can also play an important role. The nucleotide sequence can determine the stiffness of a section of DNA, which in turn affects how much the DNA strand deforms when it hooks up with DNA-binding proteins, influencing its activity.
And at larger scales, the packaging of DNA and associated proteins into a compact form called chromatin can affect whether particular genes are active or not.
None of this is well understood. But it recalls the way that early work on protein structure in the 1930s and 1940s cast around for dimly sensed principles before an understanding of the factors governing shape and function transformed our view of life's molecular machinery. In the same way, it's possible that the latest studies on the shape of DNA are hinting at some forthcoming insight that will reveal gene sequence to be just one element in the logic of life.
- Parker, S. C. J. et al. Science doi:10.1126/science.1169050 (2009).
- Miyoshi, D., Karimata, H. & Sugimoto, N. J. Am. Chem. Soc. 128, 7957-7963 (2006).
- Nakano, S. et al. J. Am. Chem. Soc. 126, 14330-14331 (2004).
- Miyoshi, D. et al. J. Am. Chem. Soc. doi:10.1021/ja805972a (2009).
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