A giant step in gene sequencing

by Sylvain Comeau

An international consortium of scientists announced a world first last week: the complete genetic sequencing or mapping of a complex organism.

After 13 years of effort, the genome of the yeast fungus Saccharomyces cerevisiae, or baker's yeast, is now known. The Yeast Genome Project united the efforts of scientists in Europe, the U.S., Japan and Canada, who divided up the task of determining the sequence of genes within the 16 chromosomes of the yeast's cells.

McGill biologist Howard Bussey, who sequenced chromosome I and pieces of chromosome XVI along with Concordia biologist Reginald Storms, has led the Canadian effort since 1991. In an interview on Monday, Bussey explained the enormous significance of the accomplishment. Since yeast is a complex organism (it has a eukaryotic cell, or cell with a nucleus), it demonstrates a remarkable similarity to humans.

"Since the second world war, and especially since the mid-1960s, there has been a strong push to study yeast as a 'model' for human cells. Humans, plants and fungi all have a common ancestor; we now have an 'operating manual' for yeast cells, which gives us information about all three."

Thus, the yeast genome provides in many ways a short cut to understanding human cells.

"We want to understand human cells, but they are very complex. So we can look at something that has all the properties of a human cell, but is somewhat simpler."

In fact, Bussey and his colleagues were surprised to learn that at least one-third of the yeast genes are remarkably similar to human genes. Bussey predicts that this revelation will give a boost to the Human Genome Project, a similar undertaking which is scheduled to be completed in the year 2001.

"This is really the first step in the Human Genome Project. That project will advance by a number of stages, with the sequencing of progressively more complex organisms. E. coli bacterium will be done very soon, then the worm C. elegans, the fruit fly, the mouse, and finally, human beings," says Bussey.

"There is an orderly progression. If we had started right away with humans, we couldn't have made any sense of it. We need simpler systems first, to do experiments to understand how the human genome works."

The correlation between yeast and human cells is also likely to produce medical applications, such as in cancer research.

"Researchers can engineer yeast genes to mutate and mimic defective, cancer-causing human genes. Yeast genes that resemble cancer genes can be studied to find out how they cause disease, and that information can be applied directly in human cells."

Another example is the cystic fibrosis gene, which has a yeast homologue. In the case of that disease alone, knowledge of the yeast genome would have saved vast amounts of time and energy.

"The human genome is 200 times more complex than the yeast genome. Doing experiments in yeast speeds up the process enormously. Finding the cystic fibrosis gene in humans cost more than $150 million dollars, and took 10 years. But if the yeast genome had been available then, one person could have found it in yeast and matched it in humans in a matter of months."

Saccharomyces cerevisiae was chosen because it is the yeast with the most uses in everyday life; it is used to make beer and bread, and to ferment alcohol. But understanding its genome provides valuable information about other types of fungi.

"Fungal infections are the most common cause of death for HIV-infected people, and a danger for anyone who is immuno-suppressed. Fungal pathogens, such as Candida albicans, are closely related to Saccharomyces. So, for example, researchers could find out from our project which genes are responsible for making the cell walls of Candida albicans, and develop drugs which inhibit the creation of the cell walls."

Bussey and his colleagues in the Yeast Genome Project have no intention of patenting the genome; in fact, they have already made it available in a data base on the World Wide Web, putting a valuable tool in the hands of numerous researchers.

"We now know the blueprint for (this kind of) yeast; no engineer would attempt to build something without the blueprint, but biologists have been struggling to understand very complicated machines without one. It's been difficult; you don't know what you're missing. For the first time, we'll be playing with a full deck, so to speak."

Bussey and Storms' work is sponsored in Canada by CGAT (Canadian Genome Analysis and Technology).