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EVERY time we break bread or drink wine, we celebrate our unique symbiosis
with yeast, that most industrious of domesticated organisms. As biologists
begin to unravel the structure of its genome they expect this venerable
relationship to intensify. Yeast is a relatively humble single-celled fungus,
but its cells and its biochemistry are similar to ours. Analysis of its
genome will undoubtedly provide many clues of vital importance to other
genome projects as well as revealing the problems that are likely to arise
in such huge ventures. Systematic sequencing of the yeast genome began in
January 1989 as part of the Biotechnology Action Programme of the European
Community. Andre Goffeau leads the project from the department of biochemical
physiology, University of Louvain, Belgium. Goffeau has called genome sequencing
the moon mission of modern biological research. If so, the yeast project
is already in orbit. ‘My goal,’ says Goffeau, ‘is to have it 50 per cent
finished in 1995.’

In the first phase of the study, an assemblage of 35 laboratories in
10 European countries is sequencing an entire chromosome (chromosome III).
At the end of 1989, half of its string of 370 000 building blocks (base
pairs) had been deciphered. ‘We’ll certainly be finished by the end of this
calendar year,’ says Stephen Oliver of the University of Manchester Institute
of Science and Technology, ‘and we’re hoping that we’ll be finished by the
summer.’ The project has already revealed scores of new genes, among them
several so unexpected that they would probably have remained undiscovered
for years without the systematic approach of sequencing.

The second phase of the project, due to last until 1994, will take on
three more chromosomes. This phase will stop short of the complete genome
– yeast cells have 16 chromosomes – but the Europeans hope that groups in
the US, Canada and Japan will sequence other chromosomes. Formal coordination
is yet to be agreed, but it is in everyone’s interest to avoid duplication.
As Goffeau says, ‘It’s a waste of money to do it twice.’ The sums involved
are not easily dismissed: the European programme, for example, has a projected
budget of 20 million ECU (1 ECU = Pounds sterling 0.74) up to 1995. At the
moment the cost is 5 ECU per base pair, but this figure will fall to 2 ECU
per base pair in the second phase of the study.

The yeast project already has an international flavour. Not only is
it dispersed throughout Europe, it also draws heavily on resources in the
US, especially on the work of Maynard Olson of Washington University, St
Louis. Olson has built a library of ordered genetic fragments from yeast,
which are propagated in bacteria. The fragments are on average about 15
000 base pairs long and each has extensive regions of overlap with its neighbours.
Scrutiny of the overlaps allows the fragments to be arranged in an order
that reflects their position on the chromosomes. Cloned DNA has also come
from Carol Newlon of New Jersey Medical School in the US.

Oliver is responsible for distributing yeast DNA to the laboratories
involved in the project. ‘People contract to do particular work units. A
work unit is 8000 base pairs of primary sequence and 3000 base pairs of
overlap checking. Most laboratories contract for either one or two such
work units,’ explains Oliver. The existence of extensive overlaps between
the fragments means that a substantial part of the genome is being sequenced
twice. ‘This provides an inherent check on the accuracy of the final sequence.’

So far, the results have been very encouraging. ‘The amount of conflict
between two people sequencing independently is of the order of one conflict
per thousand base pairs – which is really very, very good, I think,’ says
Goffeau. Sequencers deposit the results of their work in a data bank at
the Martinsrieder Institute for Protein Sequencing, near Munich, West Germany.

As well as sequencing the genome, researchers are also keen to decipher
the function of newly discovered genes. Yeast is eminently suitable for
such studies. ‘The thing I would want to emphasise about the yeast project,
perhaps in contrast to some of the other larger projects, is our ability
to very rapidly do the functional analysis,’ says Oliver. Once a gene is
cloned, researchers can disrupt its sequence, making it defective, and then
reinsert it into yeast cells. By analysing the ensuing molecular mayhem,
they often deduce the function of the normal gene.

As the work proceeds, it will bring important benefits, not least to
the brewing and baking industries. Equally significant will be the impact
on molecular biology. Yeast has a relatively small genome, a two hundredth
of the size of ours, yet it boasts around 6500 genes, the vast majority
of which remain unexplored. Those that have been described often show a
surprisingly close resemblance to the genes of other organisms, including
mammals. This resemblance stems from the fact that all cells must perform
similar molecular chores – for which they require similar biochemical tools.

Researchers will discover thousands more of these fundamental genes
in the course of the yeast project. Such discoveries will undoubtedly help
in the quest for specific human genes. For this reason, yeast makes an ideal
pioneer in the great sequencing adventure.