Yeast Underscores Complexity Of Genetic Variation Between People

Fred Hutchinson geneticist Leonid Kruglyak, Ph.D., and colleagues will report their findings in the April 26 edition of Science. Rachel Brem, Ph.D., and Gael Yvert, Ph.D., both fellows in Kruglyak's laboratory, share first authorship of the paper.

Complex traits, which range from diseases like diabetes and cancer to behaviors like violence and aggression, have been notoriously difficult to study in humans and other mammals, the systems in which most such analyses have been conducted.

While yeast provides a powerful new avenue for studying natural variation that results from complex genetic interactions, the researchers caution that even in the case of this simple fungus, the study of complex traits is likely to remain a formidable challenge in biology.

"The good news is that our method worked and that we can use it as a way to study complex traits, Yvert said. "We can expand it to the study of other organisms. The caution is that we're still dealing with a very complex system that is likely to be even more so in humans."

"Complex" diseases of civilization typically arise from a variety of inherited and acquired mutations in more than one gene. Identifying the many genetic factors underlying conditions such as cancer and heart disease poses a much bigger challenge to geneticists than rare disorders such as Huntington's disease and cystic fibrosis, which are always traceable to a single genetic defect.

To date there have been no complex diseases or inherited traits in humans for which all of the causal genetic factors have been identified. Finding multiple genetic regions implicated in any one disease or trait has been difficult because the human genome is so vast, containing some 30,000 genes through which to sift.

Yeast, while genetically and physically simpler than multicellular organisms, exhibits complex traits as well. Examples include the appearance and texture of colonies in a petri dish, and the ability to grow at high temperatures.

In contrast to humans, yeast contains only 6,000 genes - all of which have been cataloged and sequenced. Although the yeast genome is hundreds of times smaller than that of the human, it displays considerable complexity with regard to diversity of gene expression.

Just as two people can be very unique genetically, so can two yeast strains from the same species, or family. This finding allows researchers for the first time to regard yeast as a viable model for understanding complex genetic traits and diseases in higher organisms, including humans.

"Until now, people hadn't really used yeast much to study complex traits; instead they were using it to study particular biological processes, such as the genes that control cell division. But we have found that yeast also provides a great model for looking at genetic complexity in general," said Kruglyak, an associate member of Fred Hutchinson's Human Biology and Public Health Sciences divisions and a Howard Hughes Medical Institute investigator.

For the study, the researchers used DNA arrays (so-called "gene chip" technology that analyzes the expression of thousands of genes at once) to compare genome-wide expression patterns in laboratory-grown and wild strains of Saccharomyces cerevisiae (Brewer's yeast). Although from the same family, or species, the different strains of yeast proved to be highly variable in terms of gene expression.

In an analysis that involved more than a billion data-point combinations, the researchers identified some 1,500 genes that were differentially expressed between the two yeast strains, the majority of which displayed complex patterns of inheritance.

"This provides a roadmap for understanding what genetic complexity really looks like at the molecular level," said Kruglyak, also an affiliate professor of genome sciences at the University of Washington School of Medicine.

Next on the laboratory's agenda: taking a representative complex trait in yeast and identifying the entire set of genes that contribute to that characteristic. An example with relevance to human cells would be to look at a yeast cell's response to drugs used in cancer treatment.

Study co-leader Brem is enthusiastic about the power of this new approach to address mechanistic questions.

"When I go to seminars, scientists always mention that they've observed changes of gene expression in their experiments," she said. "With our system, we can begin to explain why."

The Howard Hughes Medical Institute funded the work.

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The Fred Hutchinson Cancer Research Center, home of two Nobel Prize laureates, is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Fred Hutchinson receives more funding from the National Institutes of Health than any other independent U.S. research center. Recognized internationally for its pioneering work in bone-marrow transplantation, the center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. Fred Hutchinson is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest and is one of 41 nationwide. For more information, visit the center's Web site at http://www.fhcrc.org.