A new generation of sequencing machines is broadening horizons for users. Various groups have recently performed epigenetic studies — looking at modifications to the genome that control its expression — that would have been utterly impractical using old technologies.

Sequencing machines such as the 1G are revolutionizing the speed at which DNA is analysed. Credit: C. RUSS, BROAD INST.

The latest approach fishes out all the DNA associated with a given marker, such as one of the histone proteins used to package genes in chromosomes. Then, instead of comparing each piece of DNA with a library of previously isolated sequences, as used to be done, scientists simply sequence the whole lot.

The key to this approach is new technology such as that sold by Solexa, a company that earlier this year merged with Illumina of San Diego. “The amount of DNA sequence being produced by these machines is staggering,” says Steven Jones, associate director of the Genome Sciences Centre at the British Columbia Cancer Agency in Vancouver. Working flat out, a Solexa 1G machine could triple the total amount of DNA sequence contained in the GenBank database in just one year.

Jones's group looked at histone changes that control which regions of DNA can be read1. Meanwhile, scientists from the Broad Institute in Cambridge, Massachusetts, and Massachusetts General Hospital in Boston used a Solexa machine to examine two types of histone modification in mouse cells. Their paper2, published online in Nature on 1 July, describes how these modifications change during development, and how such changes can either keep cells poised to switch fates, or close down their future options.

“The excitement about this paper is that we now have a means of studying cellular state in a high-throughout manner,” says Bradley Bernstein, a pathologist at Massachusetts General Hospital who co-led the work with Broad director Eric Lander. “We certainly couldn't have done this on a genome-wide scale before.” (See 'Sequencing revolution ushers in new era'.)

This advance is already unveiling new biology, says Keji Zhao of the US National Heart, Lung and Blood Institute in Bethesda, Maryland. Zhao's group has used it to decipher the messages encoded by two types of epigenetic mark produced by adding methyl groups to DNA3. Zhao says scientists' ability to take large-scale, complete snapshots means it might one day be possible to catalogue all the non-genetic alterations that control how genes are expressed in various cells and at all stages of development. And progress could be breakneck: Zhao's group took delivery of its first Solexa machine in January and published its results in May.

Beyond epigenetics, says Lander, other ambitious projects beckon. For example, this May, the genome of genomics pioneer James Watson was bared to the world4 after being sequenced using technology from 454 Life Sciences, a company based in Branford, Connecticut, that has just been acquired by Roche Diagnostics. This got institutions such as the US National Human Genome Research Institute thinking seriously about sequencing the complete genomes of hundreds or even thousands of people. The technology might also be used to identify new organisms, such as obscure bacteria living in complex microbial communities.

But Lander cautions that all this will take a lot of work as scientists map out how best to use the latest advances. The new technologies typically read out much shorter stretches of DNA than the older generation of sequencers did. And new methods must be developed for preparing samples and assembling these short reads into whole genomes. “It's going to be a nightmare for a year or two, as we try to fit old or important applications to these strange new platforms,” Lander says. “But the return is going to be tremendous.”