AS THE two parallel efforts to sequence the human genome enter their final
stages, the geneticists who gathered in Vancouver for last week’s meeting of the
Human Genome Organisation are already looking ahead. Many think the key to
finding the meaningful words in the three-billion-letter long sentence of our
DNA is sequencing the genome of the humble lab mouse. “That will be the Rosetta
Stone in terms of interpreting the human genome,” says Steven Jones of the
Genome Sequence Centre in Vancouver.
The company Celera Genomics, headed by Craig Venter, which is already setting
the pace in unravelling the human genome, announced it would try to sequence the
mouse genome earlier this month. Later this year, when the main publicly funded
American sequencing centres are scaling down work on the human genome, they will
start sequencing the mouse genome. The US’s National Human Genome Research
Institute estimates that it will take the ten public labs about three years to
produce a working draft.
Despite appearances, mice and humans are remarkably similar when it comes to
their DNA. Both genomes have about three billion bases, only about 3 per cent of
which codes for functional genes—the other 97 per cent being “junk DNA”.
In the many millions of years since mice and humans diverged from a common
ancestor, much of the important DNA has been conserved, while the “junk” has
mutated freely and is now very different. That means that simply comparing the
two genomes will be an efficient way of identifying vital stretches of DNA,
including genes and sequences that regulate gene expression.
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Even better, by “knocking out” selected genes in lab mice, we get a good idea
of what they do. The equivalent genes in humans should have very similar
functions. And that is the first step on the long road to finding useful
applications for all this genetic information. “When it comes to drug
development, this is crucial,” says Lap-Chee Tsui, president of the Human Genome
Organisation (HUGO).
Vancouver’s Genome Sequence Centre, part of the British Columbia Cancer
Research Centre, is starting the public sequencing effort by making a physical
map of the mouse genome—a low-resolution chart that orders known sections
of DNA and helps locate important areas of each chromosome. With that map, the
centre can decide which stretches of DNA need to be sequenced to get good
coverage of the mouse genome without unnecessary duplication. Sometime this
autumn the Vancouver lab will deal out the cards saying who should sequence
what—including data about which segments might be of the greatest medical
importance.
Celera uses a different method, known as the “shotgun technique”, in which
the whole genome is randomly broken into fragments. The fragments are then
sequenced and researchers use heavyweight computer power to spot overlapping
fragments which allow reassembly. Although potentially less accurate than
traditional “directed” sequencing along the chromosome, the shotgun approach is
considerably faster. “Ultimately it will accelerate the progress and the public
availability of information,” says HUGO’s senior vice-president Gert-Jan van
Ommen about Venter’s work.