A scientific first for Europe: the sequencing of the 6 000
yeast genes. 134 laboratories, working together in the EUROFAN project,
are adding to our knowledge of this very special living organism,
which has many genes comparable to those of humans. Their work, which
has been characterised by a particularly innovative methodology, opens
up highly promising prospects for the deciphering of genes of potential
use in biomedicine and the bio-industry.
What could be more ordinary than bread
- yet baker's yeast is creating a stir among researchers.
Because the structure of its genome, and probably at least
a third of its genes, are similar to those of man.
A complex living organism, with an elaborate
genetic make-up, yeast has been used for thousands of years in everyday
applications to make bread, beer and cheese, by artisans who used
biotechnology without knowing it. Today, baker's yeast, Saccharomyces
cerevisiae, is used widely in the synthesis of molecules on an industrial
scale and has fascinated researchers for decades.
Indeed, the yeast cell shares numerous common features with the
human cell. Its genome, divided into 16 chromosomes (but 250 times
shorter than the human genome), was completely sequenced in 1996
thanks to the European Yeast Genome Sequencing Network (EYGSN) project,
supported in large measure by the European Commission. After work
lasting seven years, a network of European laboratories with links
to American, Canadian and Japanese partners succeeded in sequencing
12.06 million bases, representing some 6 000 potential genes.
Of yeast and men
This collaborative scientific venture on a massive scale has produced
some surprising results. For instance, the structure of the yeast
genome, and probably at least a third of its genes, are similar
to those of man. Some 50% of its proteins display a sequence of
amino-acids indicating certain similarities to human proteins. Several
dozen unknown genes, which could be involved in resistance to antibiotics
and to drugs used in chemotherapy, owe their discovery to yeast.
It is also known that certain yeast species are responsible for
infections for which no satisfactory treatment exists. Accordingly,
this vast mapping operation opens up very interesting prospects
for the understanding of certain diseases - such as cancers and
Deciphering the orphan genes
This "back-to-front" approach was adopted by the researchers involved
in EUROFAN (European Functional Analysis Network) with the aim of
capitalising on the potential opportunities offered by the sequencing
of the yeast genome. Launched under the European Union's Biotechnology
Programme, this ambitious project brought together 134 laboratories
spread over 14 countries(1) in its initial phase
(1994-1998). The first task facing the researchers was to select a
thousand "orphan" genes and to attempt to analyse their function.
This huge task was organised in a particularly efficient manner. Each
team dealt with the mutagenesis of the genes assigned to it and, using
codified methods, carried out an initial series of tests. During this
stage an approximate function can be attributed to each gene, whereupon
groups of related genes or genes that are involved in the same metabolic
pathway can be routed towards the laboratory most qualified to analyse
them further. More than 800 vectors, each incorporating a turned-off
orphan gene, are used to study the latter's function. More than 350
of these genes have been isolated - i.e. cloned. The vectors and the
isolated genes will be made available to the scientists and manufacturers
by the European Centre for Genetic Archives (EUROSCARF).
However, yeast did not yield up all its secrets in the course of
the EYGSN project. Although the scientists succeeded in identifying
certain genes known as "orphans", they were unable to discover their
function. Nor were they able to link them to other known elements.
How then could they be studied? By working backwards: instead of
isolating a mutant cell in an attempt to identify the gene responsible
for this effect, systematic steps would be taken to cause mutageneses
- i.e. mutations of the targeted orphan genes - while at the same
observing what function was affected as a result.
High stakes, high outlay
"The scientific objectives of EUROFAN 1, i.e. the work on mutagenesis
and the preliminary analysis, have been achieved. The coordination
centres are operational, and the methods of analysis have been standardised.
We can now move forward with optimism to EUROFAN 2, the second phase
of the project, which is scheduled to last for two years," says
Dr Stephen Oliver of the University of Manchester Institute of Science
and Technology (UK), the scientific coordinator responsible for
"Given the scale of the scientific effort, the magnitude of the
financial outlay and the number of laboratories involved, it would
be impossible to embark on a programme like EUROFAN without real
political will," he goes on. "No country had the means to do so,
and it has fallen to the European institutions to make possible
the development of resources that will prove enormously useful to
biomedicine and the bio-industry."
Equally ambitious, EUROFAN 2 (1998-2000), brings together 79 European
laboratories.(2) Its aim: to analyse all the
6000 yeast genes. "A venture like this, on such a huge scale, demands
flawless collaboration by the various participants, each of whom
must maintain their position at the forefront of excellence and
innovation," explains Bruno André, Director of the Physiology Laboratory
of the Free University of Brussels, and involved in the project
from the outset.
A network built round a
network It is now possible to look forward to a time when we will
understand the functioning of a cell in its totality - a hitherto
unprecedented achievement. Furthermore, this project has enabled
us to establish a collaborative network of laboratories and has
created the biological and informatics tools needed to speed up
the study of much more complex organisms, such as plants and man
The creators of EUROFAN have anticipated the development of even
more ambitious projects and have evolved a structure to cope with
this task. They have taken care to ensure that the work of the scientists
will be backed up by consortia of services responsible for the administrative
coordination and development of databases and other informatics
tools designed to facilitate the use of the mass of data generated
by the project itself. A centre for the storage of cultures and
biological material needed for functional analysis purposes has
been set up. In addition, the involvement of the YIP (Yeast Industrial
Platform), a network of undertakings built up round the sequencing
project, will guarantee the rapid transfer of technology to industry.
At the industrial level, this innovative project is also producing
spin-off benefits in terms of company and job creation. Thus it
is that two German SMEs have come into being in the wake of the
involvement of researchers in the original genome sequencing project.
(1) 27 laboratories in Germany, 21 in France,
10 in Switzerland, 9 in Belgium, 1 in Greece, 8 in Italy, 17 in
Spain, 19 in the UK, 2 in Portugal, 2 in Sweden, 7 in Austria, 8
in the Netherlands, 1 in Denmark and 2 in Finland.
(2) 6 in Switzerland, 9 in Spain, 1 in Greece, 6 in Austria, 6 in
Belgium, 12 in the UK, 14 in France, 11 in Germany, 4 in Italy,
6 in the Netherlands, 1 in Finland, 2 in Sweden and 1 in Portugal.