From sourdough to schizophrenia

How geneticists are using the humble yeast to understand human disease

A recent study by scientists at U of T‚ McGill‚ and research institutions worldwide has forever changed our understanding of how our genes make who we are—and they did it all by looking at yeast‚ the humble fungus we have used for thousands of years to make beer‚ bread and wine.

How can studying such a simple organism tell us anything about the genetics of humans? Yeast actually share 33 per cent of their genes with us‚ and most of the genes we share are “essential genes‚” genes that we cannot function normally without. Dysfunction in any of these genes leads to death in yeast‚ and in humans leads to a whole host of diseases. So understanding how these genes work in yeast can help us understand the basis for many genetic human diseases‚ like schizophrenia and mental retardation.

Biologists have known for a long time that genes interact in complex ways to determine our traits‚ but “this study shows for the first time just how complex it is‚” says Dr. Charles Boone‚ who co–authored the study along with U of T professor Dr. Brenda Andrews and grad student Amy Tong.

Geneticists used to focus on trying to show how a single gene leads to a single trait—trying to find “the gene” for eye colour‚ or “the gene” for cystic fibrosis. Scientists chalked up differences between individuals to the different versions of each gene that people carry. For example‚ “blue” and “brown” are two different versions of the gene for eye colour. We each have two versions of every gene‚ one from our mother and one from our father‚ for every gene in our body. Some genes have only one form‚ so that all members of a species have two identical copies of each gene. But some genes have two‚ three‚ or even hundreds of versions. The different versions that individuals carry were thought to be responsible for the huge diversity we see in the human race.

But increasingly biologists have come to realize that the way a certain gene expresses itself varies depending on what other genes are present in the same animal. Two people who carry the exact same version of a gene for a certain trait might develop very different versions of that trait‚ depending on the rest of the genes that they carry.

In order to further investigate the problem in humans biologists would require a database of hundreds of thousands of people’s genetic make–ups and their corresponding physical characteristics. But this is currently impossible‚ so scientists are stuck researching much simpler organisms.

Dr. Boone and his colleagues studied the puzzle in yeast. Amy Tong‚ lead author of the study‚ said: “It’s really exciting—we’ve been working for over two years just on this project.”

Yeast have about 6‚000 genes. It is possible to create strains of yeast that are defective in a single gene; scientists therefore have created 6‚000 strains of yeast‚ each defective in only one gene. 1‚000 of these strains die instantly‚ so we know that 1‚000 of the genes in a yeast cell are absolutely essential for the fungus to live. The other 5‚000 strains could still live despite their one single defective gene. But the researchers then asked what would happen if you bred two yeast cells together‚ each defective in one gene‚ to create a yeast strain defective in two genes.

In order to fully investigate this question‚ Andrew‚ Boone‚ Tong and their colleagues had to cross 5‚000 strains of yeast against each other‚ creating 12.5 million doubly defective strains. “It was a lot of fun‚ but it was definitely a lot of hard work‚” said Tong.

“The cool thing about this‚” says Dr. Boone‚ “is that Tong and I got together with a local biotech company and we built some robots that allowed us to cross all the genes together systematically.” So modern automation spared the scientists the arduous task of cross breeding 12.5 million strains of fungus by hand. The result was a “genetic network‚” a kind of abstract representation of all the genes in a species and how they interact with each other. If an individual carrying two defective genes dies‚ those genes are said to interact with each other—they are probably both involved in a similar biological process‚ and when both are defective the system collapses.

They found that there were 100‚000 pairs of defective genes that caused the yeast cells to die‚ or at the very least grow very slowly. For any one gene‚ they found on average that there were 30 other genes that if present in a defective form in the same yeast cell‚ caused the fungus to die.

“This means that genetic interaction networks are very complex and very common. So we think that the genetic basis of probably most of our inherited traits are associated with pairs of [defective genes] rather than [defections] in a single gene‚” said Dr. Boone. “This has huge implications for human disease.”

“We think the importance goes beyond just a bunch of yeast people being interested in how yeast behave‚” said Dr. Andrews‚ “this also tells us how these same genes must be networked and interacting with each other in human cells. So the implications extend beyond the coolness factor in yeast.”

In order for a defective gene to seriously affect you‚ you usually must carry two copies of the defective gene; albinos for example must carry two albino copies of the gene for skin colour‚ one from the mother and one from the father. So if a defective version of any gene doesn’t show up in an individual who has a normal copy of the gene as well as the defect‚ that means that the defective version can spread throughout the population before any people are born that carry two copies of the defective version. In this way diseases can pervade a population unnoticed.

Humans possess somewhere between 30‚000 and 50‚000 genes. To cross 30‚000 individuals‚ each defective in a single gene‚ would result in 450 million people defective in two genes.

If you apply the findings of this study to humans‚ “this means something like one per cent of all humans formed will be screwed up in a particular biological system [due to the presence of two defective genes]‚ which is about the level we see of inherited diseases in the human population‚” said Dr. Boone.

“The importance of this work cannot be overstated‚” says U of T geneticist Dr. Peter Roy‚ who works on a tiny species of worm. He will be using a similar technique on his worms to uncover the genetic interaction network in that species. The ultimate goal for all these researchers is to create a genetic interaction network in humans‚ but in the meantime they must settle for studies on simpler species. Worms are far more closely related to humans than yeast‚ so what Roy finds out will bring us even closer to understanding the genetic basis for hundreds of human disease.