Unfinished sequence — the catch on 22

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Publication of the sequence of chromosome 22 (see pages 467 and 489) means that, for the first time since the Human Genome Project was proposed in the mid-1980s, researchers have an almost continuous sequence for a whole chromosome.

There is, however, a catch. The published sequence remains ‘almost continuous’ — there are still 11 irritating unsequenced gaps, accounting for about 3 per cent of the sequence. When researchers call the sequence ‘complete’, they mean they've gone as far as possible with routine methods.

Why do these gaps exist? Researchers on the Human Genome Project sequence DNA by isolating small pieces of chromosome inside bacterial clones or BACs (see previous page) which multiply to produce sequenceable quantities of the DNA segment. But, for various reasons, clones for certain sequences are simply absent from the collection of clones, or ‘clone libraries’.

According to Ian Dunham of Britain's Sanger Centre, the head of the team that sequenced chromosome 22, most of the gaps contain a sequence that is not stable in Escherichia coli or yeast. One gap does have a corresponding clone; but, for some unknown reason, researchers are unable to sequence it.

As Peter Little, of Imperial College London, puts it, many pieces of DNA “do really weird things when you try to work with them, and we have no idea why”.

Based on what he has seen in chromosome 22, Dunham speculates that missing sequences will tend to occur in certain regions of chromosomes: clustered at the ends, for example, with some gaps at the centres involving repeated sequences.

“The good news is that we can now see how big the gaps are,” says Dunham: they are between 50 and 150,000 base pairs. If an interesting gene is thought to be in one such gap, many strategies currently being developed could close these gaps.

“It's a matter of fiddling — there is no reason to suppose these pieces cannot be done,” says Little, adding that it would make very little difference to the overall list of genes on this particular chromosome.

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Loder, N. Unfinished sequence — the catch on 22. Nature 402, 448 (1999) doi:10.1038/44900

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