Breakthrough in profiling of yeast genome

McGill researchers key players in discovery that could lead to better drugs for human disease

An international team of researchers is publishing the results of the first-ever comprehensive genetic profiling of any organism, in this case yeast, which has proved a successful model for understanding the basic functions of human cells.

The July 25 issue of the scientific journal Nature includes an article entitled, "Functional profiling of the Saccharomyces cerevisiae genome." Canadian authors include a team led by McGill University Biology Professor Howard Bussey and Reginald Storms of Concordia University's Biology Department.

Bussey explains that human cells have the same basic cellular plan as yeast, but yeast is far more amenable to genetic manipulation. By creating a mutant strain (each missing a particular yeast gene) for 95 percent of the 6,000 yeast genes, the international project now allows genetics to be practiced on a comprehensive scale. Previously, the main route to a genetic understanding of gene function was limited to the study of a handful of genes at a time.

Bussey says the work of the international consortium could lead ultimately to the discovery of better drugs for the treatment of human disease -- not only drugs to treat fungal infections, but also drugs that act on gene products shared by the yeast and human genomes. These common genes are implicated in a wide range of diseases including certain forms of cancer. Bussey says even the researchers themselves were skeptical, at first, about their chances of success in making global mutant sets and profiling the entire yeast genome. "The results are mind blowing," he says.

Once the mutations were created -- the McGill team was responsible for about 10 percent of the exercise -- they were tagged with short bits of DNA unique to each mutation. This bar coding system allows researchers to see which mutants survive under different conditions when all mutants are pooled and grown together. It is also possible to study the effects of mutations in individual genes in more traditional approaches.

Thanks to the project's main grant, from the National Institutes of Health in the U.S., the complete collection of mutations is available to interested researchers at cost. While Bussey says he has the collection of thousands of mutants "in my fridge", the distribution of the collection is too complicated to be undertaken by each lab involved in the project and has been contracted to two companies, one in the U.S. and one in Europe.

Bussey was also part of the international effort to establish the complete DNA sequence of yeast, which achieved success in 1996, five years ahead of the publication of the draft human genome sequence. His work on the yeast genome disruption/profiling project received support from the Medical Research Council of Canada, and continues with support from Genome Canada/Genome Quebec to examine large-scale genetic interactions.

He was one of six principal investigators in the yeast-profiling project, which included researchers from universities and pharmaceutical labs in the U.S., Belgium, Germany, Italy, Spain and Switzerland. He estimates that there are 5,000 researchers working directly with yeast and many others who use yeast as a "test bed" for human genes. While functional profiling of the human genome is still far down the road, the work of the yeast global mutant profiling project is now being taken up with other organisms, such as pathogenic bacteria and fungi, and nematode worms.