The history of the yeast genome
It has been ten years since the journals Science
and Nature announced the first complete
sequencing of the genome of a single-cell eukaryote
organism. This scientific breakthrough, based on the
collaboration of several hundred European, North American
and Japanese researchers, marked the start of molecular
biology in the revolutionary age of the genome. A flash
back follows on this remarkable feat initiated by the
European Commission, the anniversary of which is celebrated
| Saccharomyces cerevisiae yeast in the process of cell division, with numerous scars from previous budding processes. Many were amazed, during sequencing of its genome (1996), to find that yeast had almost 50% of its genes identical or similar to those of man. The ‘human’ aspect of yeast or the ‘primitive’ aspect of man?
There was already talk of a project considered to be of Himalayan proportions, namely the deciphering of the human genome. Starting modestly, with yeast, it appeared to us to be a more accessible way of obtaining the genetic mapping of a complex organism,” recalls André Goffeau, a biologist at the Catholic University of Louvain (UCL – BE) as well as the Founder and Coordinator of the “European Yeast Genome Sequencing Network” (EYGSN). “We started off by mobilising numerous laboratories around this common objective. It was an exciting adventure that forged human and technological bonds within two communities, that of molecular biologists and that of IT specialists.”The idea was formed in 1986. The project was supported to the tune of €20 million by the European Union.
"The choice of Saccharomyces cerevisiae carried a certain symbolism. To produce bread, beer or wine, recourse to yeast is a pioneering biotechnological practice that dates way back in human history. But the fact is that this micro-organism also offered a totally suitable subject for research. As with all eukaryotes (including ourselves), genetic information is in fact located in the nucleus and the mitochondria of the cell. Widely used as a standard organism, yeast is an ideal tool for identifying fundamental eukaryote mechanisms – such as condensation, recombination or segregation of chromosomes during cell division or the genesis of mitochondria – essential information for understanding the processes at work in human cells.
Methodological and conceptual contributions
Some six hundred scientists from 92 European and four
American, Canadian and Japanese laboratories participated
in the adventure. Under André Goffeau’s
supervision, thirteen geneticists coordinated the impressive
project, aimed at reading the sixteen yeast chromosomes.
After work encompassing a period of seven years (1989-1996),
the project had sequenced 12 million bases, representing
some 6,000 potential genes. This work will be the subject
of articles in the journals Science
For Bernard Dujon, Scientific Director of the Pasteur Institute, whose “Molecular Genetics of Yeasts” unit has coordinated 15% of the sequencing,
“this project constituted both a pioneering project at scientific level and an achievement for European collaboration. A complete tour of the
genome has specifically afforded us the possibility, on a methodological level, of making progress in the development and automation of
sequencing techniques and having recourse, for example, to DNA chip technology from the outset. As far as conceptual developments are
concerned, the sequencing of yeast has given rise to new questions and new approaches. Why, for example, were so many genes completely new,
not expected before the sequencing, and without an identifiable function? Why were so many genes duplicated? We now know the answers to these
questions but, as is always the case in real research, the route taken to reach this goal was not a direct one. Why, for example, do certain
genes become active at certain precise moments? Thanks to the chips, it is possible to define the transcriptome of a cell (or a tissue), that is to
say, measure the state of expression of all of its genes. Consequently, experimental systems developed with regards to yeast have led, for example,
to the identification of certain molecular mechanisms of cancer.”
Another key member of the team for this vast undertaking, Jean-Luc Souciet, a lecturer at Louis Pasteur University in Strasbourg (France), is currently
coordinating the French Génolevures (CNRS) project, focusing on comparative genomic studies involving several types of yeast. For him,
“the EYGSN project marked the start of a revolution in European and international biological research. Its network organisation has allowed
laboratories from different cultures to overlap. Many of us have formed partnerships which have resulted in new discoveries. The positive effects
of this project are being felt within the community of researchers to this day.”
A basic inventory
As announced in 1990 by Piotr Slonimski, former director of the CNRS Genetics Laboratory at Gif-sur-Yvette (FR), there is nothing to prevent the inclusion of the first sequencing of a simple eukaryote organism such as yeast in the tradition of the major fundamental scientific inventories to which Kepler, Linné or Mendeleyev have contributed. The sequencing of yeast has served as a catalyst for enormous development, which has extended to the conquering of the genome of so-called “standard” organisms – such as numerous bacteria and archaea, the worm Coenorhadiptis elegans, the cress plant Arabidopsis thaliana, the fly Drosophila melanogaster, the mouse, and even (quite recently) the chimpanzee and many others. Almost 400 genomic sequences, mostly bacterial, are now available. Of these, a large number have been selected for medical or economic reasons – such as the tuberculosis bacillus, the pathogenic yeasts of plants or animals, bacteria affecting the dairy industry, rice (staple foodstuff for half of mankind) – or purely scientific reasons (understanding evolution and biological diversity).
Going back in time
Sequencing alone is not, however, enough to understand how genomes work. The progress made in molecular genetics has opened the way for new disciplines, encouraging the shift from structural genomics to functional genomics, which studies the functions of the different gene products as well as their interactions. Rapid progress in the sequencing of genomes and in silico analysis has brought comparative exploration of the living world (comparative genomics) to the forefront of production methods for knowledge that forms the basis for fundamental new discoveries.
“By comparing the genetic sequences of different yeasts, we have discovered a great deal regarding the functions of genes,” Bernard Dujon explains. “Comparative genomics also allows us to go back in time to study the evolution of species and shed light on the mechanisms that are responsible for it. We have a better understanding of how genes are born and die and, consequently, how biological functions change in different evolutionary lines over the thousands of generations that follow. By way of an example, man and certain primates have, as a result of mutation of the corresponding genes, lost the ability to synthesise vitamin C (ascorbic acid); whereas, most closely related animal species are capable of carrying out such synthesis and, therefore, never develop scurvy, whatever their dietary regime. It is possible to see how history – that is to say the accidental loss of genes in our direct ancestors – affects our present lives, that is, the need for food containing vitamin C in human beings, but not in other species. With yeast, it is possible to broaden the spectrum of these studies to billions of generations, and observe phenomena that the human genome is unable to reveal on its own. Our ability to decipher complete genome texts provides biology with a new enlightenment, which encourages a new intellectual synthesis between the two roots of the living world – function and history.”
(1) To mark this anniversary, a scientific conference took place in Brussels in September 2006.