RNAi update-Researchers Map Circuitry of Yeast Genes Using Technique that Could

[Guest guest]

Researchers Map Circuitry of Yeast Genes Using Technique that Could

Be Applied to Humans

09 May 2005 Medical News Today

Researchers at UCSD have invented a technique that organizes the

genetic information contained in the 16 chromosomes of the yeast

Saccharomyces cerevisiae into a wiring diagram resembling an

electronic circuit board. An analogous diagram of the human genome,

when developed, is expected to help in the discovery of the genetic

basis of many diseases.

In a paper published in the May issue of Nature Biotechnology,

professor Trey Ideker and graduate student Kelley reported that

their new approach allowed them to predict new functions for 343

yeast proteins based on their positions in the new wiring

diagram. " Beyond deciphering the circuitry of a yeast cell, our

analytical approach can be applied in humans to find what years of

research using other methods have failed thus far to uncover:

combinations of genes that are the true culprits in many diseases, "

said Ideker, a professor in the s School of Engineering's

Department of Bioengineering.

Ideker and Kelley designed their technique to take advantage of an

expanding library of interactions of yeast genes. Discovering such

interactions has been made possible by a new type of automated

experiment in which yeast strains with one harmless mutation are

mated with an array of other strains, each carrying a different

harmless mutation. The experiments are designed to find double-mutant

daughter cells that fail to grow. Such fatal genetic interactions in

yeast are thought to mimic the underlying basis of human diseases in

which combinations of mutated genes, rather than mutations of single

genes, are at fault.

Geneticists have traditionally studied yeast because it grows rapidly

and each stage of its cell cycle is easy to visualize. Scientists

have also found many homologs of yeast genes in all eukaryotes,

ranging from the worm and fruit fly, to humans. To date, roughly 30

percent of mutated genes implicated in human disease have yeast

homologs, a finding that leads researchers to believe that mutated

pairs of genes that cause the death of yeast cells could have disease-

causing homologs in human cells.

The UCSD researchers made use of several libraries of scientific

information about yeast, such as the known physical assemblages of

proteins, protein-DNA complexes, and metabolic networks involved in a

variety of cellular processes.

Ideker and Kelley pieced together their yeast circuit board based on

more than 4,800 cases in which a lethal effect was caused by two

mutations together, called synthetic lethal interactions. " We took

the classical approaches that have been used to analyze synthetic

lethal interactions, but we created a method to automatically

categorize these interactions, " said Kelley. " We then took this

automatic categorization scheme to determine the wiring diagram for

yeast. "

The UCSD researchers plan to refine their circuit diagram of yeast as

more synthetic lethal interactions become known. Their eventual goal

is to use the approximately 200,000 potential synthetic lethal

interactions and other information about the physical interactions of

yeast proteins to generate a computer model of a living yeast cell.

Ideker believes that the eventual wiring diagram of human cells will

be similar to that of yeast; however a newly developed technology is

needed to verify his theory. " You can't probe human cells as easily

as we can yeast, but RNAi [RNA interference] lets you target pairs or

triplets of genes, " said Ideker. " This approach in humans, patterned

on yeast experiments, could eventually lead to more sophisticated

drugs and gene therapies based on taking down not single genes, but

combinations of genes that cause disease. "

Kelley and Trey Ideker, " Systematic Interpretation of Genetic

Interactions Using Protein Networks " (2005). Nature Biotechnology. 23

(5). pp 561-566.