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Genetic revelations

Human Biology Division researchers probe yeast for clues to genetic variation
Erin Smith and Dr. Leonid Kruglyak study yeast
Erin Smith and Dr. Leonid Kruglyak examine a plate of yeast, their organism of choice for studies on genetic variation. Photo by Todd McNaught

The lowly Saccharomyces cerevisiae once again has proved that it is more than merely an essential ingredient in a loaf of sourdough or a carafe of cabernet.

New research from Dr. Leonid Kruglyak's laboratory finds that the yeast-cherished as a model microbe by geneticists for its similarity to human cells-reveals much about the enormous amount of variation that exists among individual members of a species, which affects everything from appearance to disease susceptibility.

Using yeast as a system to probe genetic diversity, researchers found that a significant portion of differences can be traced to a handful of genes, each of which controls the activity of a large number of other genes.

Because genetically distinct strains of yeast can be mated and the genetic blueprints of their offspring easily interpreted, the scientists were able to map the chromosomal neighborhood of most of these genetic circuit breakers and determine the identity of a few.

Although the researchers expected that most of the variability-controlling genes would code for proteins that bind to DNA and directly control the expression of other genes, they found that the control genes were of many types not previously thought to regulate gene activity, said Kruglyak, an investigator in the Human Biology Division.

"We were surprised that transcription factors (DNA-binding proteins that regulate gene expression) did not represent the majority of genes responsible for variation," he said. "Nobody had looked at this before."

The unexpected results provide strong support for the power of yeast genetics to uncover previously unknown elements that contribute to variation and may lay the groundwork for similar strategies in more complex organisms.

The study is published in the September issue of Nature Genetics. Co-authors include Dr. Gael Yvert, Dr. Rachel Brem, Jaqueline Whittle, Dr. Joshua Akey, Dr. Eric Foss, Erin Smith and Rachel Mackelprang.

The work builds on earlier research from the Kruglyak lab to develop a method in yeast to study complex traits, which typically arise from inherited mutations in more than one gene. In humans, most diseases, including diabetes and cancer, are the result of the interplay of multiple inherited mutations and environmental factors.

Wild versus lab-grown yeast

The researchers used tools known as DNA arrays to compare genome-wide expression patterns in a lab-grown strain and a wild strain of Saccharomyces cerevisiae, as well as their offspring. Although from the same species, the different strains of yeast are 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.

They found about 600 sets of two or more genes whose expression patterns were similar and, using a method known as genetic-linkage mapping, determined that each set of co-expressed genes was regulated by one or a few controlling genes. Altogether, about 1,700 genes-about one-third of the yeast genome-were subject to this form of control. The researchers were able to determine the chromosomal location of most of the master regulators, which they estimate total between 100 and 200 genes.

Although the researchers expected that the majority of the variation-controlling genes would be transcription factors, which are well known for their role in gene regulation, Kruglyak said that no particular class of genes was over-represented in their analysis. Other classes included a variety of metabolic enzymes that chemically modify other molecules in the cell, signaling molecules and factors that bind to RNA.

"We're not sure why transcription factors did not make up the majority of the genes we identified," he said. "It could be that variation in many transcription factors affects their function to the level that cells can't survive and therefore was selected out during evolution. Another possibility is that sets of genes are under the control of multiple transcription factors that work together, and variation in any one is so minor that we can't detect it. Transcription factors also represent only a fraction of the network of factors that control gene expression."

Variation in expression

The scientists also took an in-depth look at two of the controlling factors they identified, called GPA1 and AMN1, in order to identify the sets of genes whose expression was under their regulation.

GPA1 is involved in transmitting signals within the cell when yeast respond to pheromones, small molecules which induce sexual reproduction between opposite "mating types" of yeast. AMN1 had been known to play a role in cell division. The researchers found that the DNA sequences of GPA1 and AMN1 differed between the lab and wild yeast strains and accounted for variation in expression of the subsets of genes that each regulates.

Their analysis of AMN1 revealed a previously undescribed function of the gene. The wild strain, which has a functional version of the gene, incompletely separates newly divided cells, causing them to exhibit "clumpy" growth. The lab strain has a defective version of AMN1 and does not grow in clumps, making it more desirable for experimentation.

"Many desirable traits have been bred into laboratory strains by biologists," Kruglyak said. "This raises an interesting question about whether what is discovered in laboratory strains can be broadly generalized and underscores the importance of studying wild strains as well."

The National Institutes of Health, the Howard Hughes Medical Institute, the James S. McDonnell Foundation and the Human Frontier Science Program provided funding for this study.

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