Photo by Michelle Hruby
Researchers in the Human Biology Division have harnessed the power of yeast as a model to study trait inheritance and the genetics of complex conditions and characteristics at the most basic, molecular level.
Dr. Leonid Kruglyak and colleagues developed a novel system to study the architecture of characteristics that result from the interplay of multiple genes. The system uses DNA arrays, gene chips that allow the expression of thousands of genes to be monitored simultaneously,.
Complex traits, which include diseases like diabetes and cancer and behaviors such as violence or aggression, have been notoriously difficult to study in humans and other mammals, the systems in which most analyses have been conducted.
Yeast - the single-celled organism crucial for brewing beer and baking bread - provides a powerful new avenue for studying natural variation that results from complex genetic interactions. But 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 study, published in the April 26 issue of Science, was led by postdoctoral fellows Drs. Rachel Brem and Gael Yvert.
"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 complex system that is likely to be even more so in humans."
"Complex" diseases of civilization, such as cancer, diabetes and heart disease, typically arise from a variety of inherited and acquired mutations in more than one gene. Identifying the many genetic factors underlying such conditions poses a much bigger challenge to geneticists than rare disorders such as Huntington's disease and cystic fibrosis, which are traceable to a single genetic defect.
To date, no complex diseases or inherited traits in humans have surfaced in 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.
While genetically and physically simpler than multi-cellular organisms, yeast exhibits complex traits as well. Examples include the appearance and texture of colonies and the ability to grow at elevated temperatures.
But in contrast to humans, yeast has 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 from the same family can differ genetically, so can two yeast strains from the same species.
The finding by Brem and Yvert 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," said Kruglyak, a Howard Hughes Medical Institute investigator. "Instead, they use 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."
For the study, the researchers used DNA arrays to compare genome-wide expression patterns in lab-grown and wild strains of Saccharomyces cerevisiae (Brewer's yeast). Although from the same family, or species, the different strains of yeast proved highly variable in terms of gene expression. Because the output of many genes is modulated by the actions of other genes, the team reasoned that gene expression in and of itself can be an example of a complex trait.
In an analysis that involved more than a billion data combinations, the researchers identified more than 1,500 genes that were differentially expressed between the two yeast strains, the majority of which displayed complex inheritance patterns. This finding supports the validity of using yeast as a model to study complex traits and diseases in higher organisms.
"This provides a road map 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 lab's research agenda is to take a representative complex trait in yeast and identify the entire set of genes that contribute to that characteristic. An example with relevance to human cells, Yvert said, would be to look at a yeast cell's response to drugs used in cancer treatment.
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."