New & Noteworthy

Yeast, More Interesting than your Parents Think

April 23, 2013

Are you tired of getting asked why you study yeast? And having your grandma’s eyes glaze over when you try to explain your latest research result to her? Well, we here at SGD have decided to help you out.

We have revamped our “What are yeast?” page to make it even better. We’ve stripped out a lot of the jargon making it much simpler for the nonscientist to read. Not only that, but we’ve consolidated the information onto a single page so you won’t have to link out so much to find what you are looking for.

So now when your mom asks why you’re wasting your time on yeast, you don’t have to tear your hair out and try to explain it to her. We’ve done the work for you.

You can send her to our reworked page where she can see what makes yeast such an ideal organism to study. She’ll learn that we share a whole lot with yeast even though they are single-celled. Our cells are set up similarly, we share lots of the same genes, and yeast are way easier to grow and manipulate than a person. She’ll see we’ve learned a lot about cancer, Alzheimer’s, Lou Gehrig’s Disease, and so on from our little friends. She’ll learn how useful they are for making existing medicines better and finding new ones. And that’s just a couple of the sections!

After reading this, your friends and family will realize there is much more to yeast than making bread or wine (although these are awesome as well). They will see how useful yeast is for understanding us and they will have a newfound respect for the work you do. At least we hope they will!

Categories: Website changes

Community Wiki Updated

April 22, 2013

SGD’s Community Wiki now has a new look and a clearer organization, making it even easier for you to share important information with the yeast community.  Use the wiki to record facts about your favorite gene, post a job opening or meeting announcement, or add links to yeast resources. Please contact the SGD help desk for an account that will allow you to log in and add to the wiki.

Categories: Website changes

When Half a Loaf is Too Much

April 18, 2013

One of the ways you can tell a human cell is cancerous is by taking a peek at its genome. Instead of the orderly 23 pairs of chromosomes seen in a normal cell, the cancerous one has a jumbled mess of a genome. There are extra chunks sticking here and there, chunks missing, and lots of other oddities.

Besides looking untidy, this sort of chaos also causes something called copy number variation (CNV). In CNV, there are either more or less than the usual two copies of some genes. Having the wrong number of copies of certain genes can definitely cause problems.

There is some debate out there about whether CNV causes a cell to go cancerous or if it is just an effect of the cancer. In a new study, de Clare and coworkers provide strong evidence that for many genes in the yeast Saccharomyces cerevisiae, having just one copy in a diploid background leads to faster growth, poor cell cycle control, and an aversion to apoptosis (programmed cell death). This argues strongly that CNV can actually cause a cell to go cancerous. This suggestion is strengthened further by the fact that many of the genes they identified are orthologs of human genes that exist as single copies in certain cancers.

Earlier studies from this group looked at the growth rates of over 5,800 heterozygous diploid yeast mutants, each missing one copy of a particular gene, and found around 600 that actually grew faster than wild type. You might not expect such a high number at first blush, since it seems like a single celled organism would have evolved to grow as fast as it can. The authors hypothesized that there must be a strong selective advantage to having these genes, outweighing the fact that they slow down growth.

Looking more closely, they found that the genes in this set were significantly more likely than the average gene to have functions that keep the genome stable, such as DNA damage repair. They were also highly conserved across the Ascomycete fungi, confirming their importance.

The next step was to see whether there might be any connection to human cancer. They took a subset of these genes – 30 genes involved in DNA repair and sister chromatid segregation – and compared them to human genes. Nineteen of the yeast genes had a human ortholog, and 17 of those human genes exist as a single copy in many cancers, suggesting that having only one copy of these genes may contribute to a cell’s cancer phenotype.

If copy number variation of those genes contributes to cancer in human cells, does it confer a cancer-like phenotype on yeast? The researchers found that the heterozygous yeast mutants showed characteristics of cancer cells such as altered cell cycle, a decrease in apoptosis, and lowered sensitivity to anti-cancer drugs. So the increased growth conferred by the mutations comes with a high cost: increased genome instability and cancer-like symptoms.

Because this cancer-like phenotype occurs in yeast, it will be an excellent model to study exactly how particular genes contribute to it. But these findings could also have a more immediate impact on cancer treatment. Certain experimental cancer treatments work by decreasing the activity of the proteins produced by some of these genes. If a treatment only partly knocks down the activity, then it may actually encourage cancer growth. It would mimic the effects of having a single copy of a gene. The authors actually show that this is the case in yeast for some of the drugs they tested.

And this isn’t a worry just for the drug targets themselves. The drugs aren’t completely specific…they can affect other genes too, again mimicking the effects of having a single copy of one of these other genes. Add to this the fact that each genomically jumbled cancer cell may have different proportions of genes, and you have quite a mess. As usual, yeast can swoop in and save the day.

Scientists may be able to use this and other yeast libraries to quickly screen varying amounts of potential new drugs for their effects on growth. Not only that, they’ll be able to identify what pathways these drugs are hitting in addition to the one(s) that are targeted. This should make the process of drug optimization move ahead much more quickly. Thanks yeast!

by D. Barry Starr, Ph.D., Director of Outreach Activities, Stanford Genetics

Categories: Research Spotlight, Yeast and Human Disease

Finally, Microbes Get the Recognition They Deserve

April 15, 2013

Anyone reading the SGD blog knows that the yeast Saccharomyces cerevisiae is an amazing little organism. Not only does it give us bread, wine and beer, but it also is an invaluable tool in understanding human biology. It has helped us better understand cancer, Alzheimer’s, and lots of other diseases, not to mention basic biological processes like gene regulation and cell cycle control. This little one celled beast is the rock star of biology!

And now, finally, government is starting to take notice. In a 58-0 vote, the Oregon House recently decided that yeast should be the official state microbe. If the Senate and the governor agree, then yeast will be getting the recognition it deserves. Take that, C. elegans, Drosophila, and all of you other model organisms!

Unfortunately, this recognition is not for yeast’s scientific value. Craft beer making is huge in Oregon, and designating yeast as the official state microbe is a way of celebrating this important state industry. Given all of yeast’s other important contributions to the well-being of us all, this feels a bit like celebrating Hugh Jackman for his role as Wolverine in X-Men while ignoring his roles on Broadway or his role as Jean Valjean in Les Miserables. Yes, he was great in X-Men, but that is an incomplete picture of him as an actor. Same thing with yeast.

Yeast should be celebrated for wine and bread, for medicines like anti-malarials and antifungals, for the deep biological understanding it has given us, and even for its possible future as a source for biofuels. Still, this honor is way better than nothing, and at least yeast will be the first microbe officially recognized by a state. Well, it will be if Oregon hurries.

Hawaii is voting on an official state microbe too, Flavobacterium akiainvivens. This bacterium was discovered by a high school student during a science fair project and is only found in the state of Hawaii. The Oregon senate should vote soon, or yeast will be the second officially recognized microbe.

Of course, the bill could die in the Senate. This is what happened in Wisconsin back in 2009 when their House passed a bill making Lactococcus lactis the official state microbe. This bacterium is important for making Wisconsin’s famous cheese but it wasn’t important enough for the Senate to approve it as Wisconsin’s official state microbe. Hopefully Oregon won’t make the same mistake with yeast.

by D. Barry Starr, Ph.D., Director of Outreach Activities, Stanford Genetics

Categories: Research Spotlight

Tags: beer, Saccharomyces cerevisiae

Carl Singer Foundation Established

April 12, 2013

Carl Singer, who was an integral part of the yeast research community for many years, passed away on February 8, 2013. Throughout his career, Carl supported yeast research both with his engineering expertise and with his good cheer. In tribute to Carl, the Singer family has now set up The Carl Singer Foundation, a charitable foundation dedicated to supporting scientific education in the field of yeast genetics. Questions about the foundation may be directed to Harry Singer at harry@thecarlsingerfoundation.org.

Carl’s family would be happy to receive memories of Carl’s life at regards@singerinstruments.com.

Categories: News and Views

The Indulgent Chaperone

April 01, 2013

When you think of a chaperone, you probably think of a strict adult at the prom who keeps a tight rein on the kids’ behavior.  Well, in nature, a chaperone sometimes has to do the opposite to help new genes form more quickly.  Sometimes the chaperone has to give the gene a longer leash to explore lots of different possibilities.

See, in theory, it is pretty easy to make a new gene.  A cell accidentally makes an extra copy of an existing gene and this gene is then free to mutate into something new.  A few mutations later and you have a new gene.

Turns out this is probably trickier than it sounds.  First off, having an extra copy of a gene can cause problems.  And second, getting to a new function is no walk in the park either.  It usually takes a few sequential mutations to get there and, with proteins being such persnickety things, many of the intermediates along the way end up being unstable. 

One way a cell might deal with these issues is to bring in a chaperone that lets the gene tolerate more mutations.  Chaperones are proteins that help stabilize other proteins, often under trying conditions like high temperature.  They coddle the protein and keep it stable so that it can still do its job.  In addition, chaperones can also cause a protein to relocate to different parts of the cell.

So the idea is that if a duplicated gene gains a mutation that lets its protein interact with a chaperone, the protein may get more stability from that interaction or may be rerouted to where it won’t do any harm. Because the chaperone buffers the possible harmful effects for the cell, the gene is free to explore more different intermediates on the way to its new function.

A new study out in GENETICS by Lachowiec and coworkers lends support to this “capacitor hypothesis.”  The authors used both Arabidopsis and Saccharomyces cerevisiae to show that genes whose proteins interact with the chaperone Hsp90 evolved more quickly than closely related genes that did not.  This strongly supports the idea that chaperones can encourage new functions in duplicated genes.

The authors first looked at a couple of closely related transcription factors from Arabidopsis, BES1 and BZR1.  Using a specific inhibitor of HSP90 called geldanamycin (GdA), they were able to show that BES1 was a client of HSP90 but BZR1 was not.  They then created a phylogenetic tree of Arabidopsis BZR/BEH gene family and, by determining the ratio of non-synonymous to synonymous changes, found that BES1 had a higher rate of mutation.  One explanation is that the stabilizing/relocalizing influence of HSP90 allowed BES1 to tolerate more mutations.

This result was an excellent first step in showing that the capacitor hypothesis may be true in some cases, but it is limited by being based on a single pair of proteins.  To broaden their findings, Lachowiec and coworkers took advantage of the vast knowledge about Hsp90 interactions in Saccharomyces cerevisiae to look at many more genes.

At first this didn’t work out that well.  The authors looked at a data set of yeast proteins that interacted with Hsp90 (encoded in yeast by the HSP82 and HSC82 genes) and, after removing any co-chaperones from the set, found no difference in the rate of evolution between those proteins that interacted with Hsp90 and those that did not.  But as the authors note, this isn’t surprising as so many other factors play a role in the rate of evolution too.

To refine their analysis, they mimicked their BES1/BZR1 study and focused on pairs of closely related proteins where one interacted with Hsp90 and the other did not.  They found that proteins that interacted with Hsp90 had a “longer branch length” than did their close relatives that did not interact.  In other words, Hsp90 appeared to help along the formation of a new gene.

The authors then went back to Arabidopsis and showed that BZR and BES1 were found in distinct but overlapping parts of the cell.  This lends credence to the idea that chaperones cause proteins to localize to different parts of the cell. 

So it looks like an important function of chaperones may be to shepherd new gene formation.  They are more like a 1960’s version of a chaperone…they let duplicated genes make lots of mistakes on their way to discovering who they really are.

by D. Barry Starr, Ph.D., Director of Outreach Activities, Stanford Genetics

Categories: Research Spotlight

Tags: chaperones, evolution, Saccharomyces cerevisiae

Thinking Inside the Box (or Mitochondrion)

March 28, 2013

The mantra in real estate is that location is everything. The same may be true for some cases of bioengineering. You may not get the best yield unless a whole pathway is in the right cellular compartment.

This is what Avalos and coworkers found for synthesizing branched chain alcohols in the yeast Saccharomyces cerevisiae. These scientists were able to increase yield by 260% by putting the whole pathway of enzymes into the mitochondrion. This is way better than anything anyone else has been able to achieve.

This matters because branched alcohols like isobutanol may prove to be better biofuels than ethanol. We can get more energy out of isobutanol than we can out of ethanol…it has more bang for the buck. Good idea in theory, but producing large quantities of isobutanol has not worked too well in practice.

Yeast is just not very good at making these alcohols, and efforts to improve yields have been anything but inspiring so far. Overexpressing the enzymes in the metabolic pathways that generate isobutanol increased yield by only about 10%. Unfortunately, 10% of almost nothing is still pretty close to nothing.

One of the key metabolic pathways involved in generating isobutanol and other branched chain alcohols is split between the mitochondria and the cytoplasm. Normally, the valine biosynthesis pathway converts pyruvate to valine and alpha-ketoisovalerate in the mitochondria; then those two intermediates, after transport to the cytoplasm, are further converted to isobutanol by the Erlich pathway for valine degradation. Avalos and coworkers reasoned that the failure to increase yield might be because of some rate limiting step in getting the intermediates from the mitochondria to the cytoplasm. And it looks like they may have been right.

They compared the effects of overexpressing the pathway enzymes in the cytoplasm and mitochondria and found the mitochondrial approach won hands down. Overexpression in the cytoplasm bumped yield up 10% while overexpression bumped it up 260%. And this increase wasn’t just for isobutanol. Yields of two other energy rich alcohols, isopentanol and 2-methyl-1-butanol, also went up significantly.

Part of the explanation almost certainly has to do with transport of intermediates between the mitochondrion and the cytoplasm, but that may not be the whole story. The mitochondrion might be a useful environment for other reasons too. For example, its smaller volume means an increase in the concentration of reactants, and its higher pH, lower oxygen content, and more reducing redox potential may be better for certain reactions. It also contains many key intermediates like heme, steroids, biotin and so on.

On the way to improving isobutanol yield, these scientists made it easier for others to test whether moving their pathway to the mitochondria can help increase the yield of their favorite metabolite. Avalos and coworkers created a system of plasmids that easily allows researchers to attach the N-terminal mitochondrial localization signal from Cox4p, subunit IV of the yeast cytochrome c oxidase, to genes of their choice. This will make it much simpler to test whether a pathway’s yield is enhanced by moving it into the mitochondrion.

These results show there is more to increasing yield than overexpression or codon optimization. Sometimes scientists need to take a good hard look at their particular pathway and think outside of the box for new ways to optimize yield. Or sometimes they just need to think within the box that is the mitochondrion.

by D. Barry Starr, Ph.D., Director of Outreach Activities, Stanford Genetics

Categories: Research Spotlight

Tags: biofuel, mitochondria, Saccharomyces cerevisiae

Carl Singer, 1945 – 2013

March 25, 2013

It is with great sadness that we note the passing of Carl Singer on February 8, 2013. Carl was a staunch supporter of the international yeast community. His good humor, generosity and infectious enthusiasm have been bright highlights of every yeast meeting for many decades. His creativity and engineering prowess have exerted a similarly powerful impact in labs world-wide, contributing to the quality of yeast research and the ease of performing it. He will be sorely missed.

Please send memories celebrating his life to his family at regards@singerinstruments.com. A celebration of Carl’s life will be held at 2 PM on Tuesday, March 26th, at St. Michael’s Church, Minehead, UK.

Thanks to Terry Cooper for drafting this obituary.

Categories: News and Views

Hate the CIN, Love the CINner

March 21, 2013

At first our favorite small eukaryote, S. cerevisiae, might not seem like a great model for cancer studies. After all, budding yeast can’t tell us anything about some of the pathways that go wrong in cancer, like growth factor signaling. And it clearly can’t help explain what happens in specific tissues of the human body. But in other ways, it actually turns out to be a great model.

For example, all the details of cell cycle control were originally worked out in yeast.  And now a whole new batch of genes has been found that influence a phenomenon, chromosome instability (CIN), that is important in both yeast and cancer cells.

As the name implies, chromosomes are unstable in cells suffering from CIN. Big chunks of DNA are lost, or break off and fuse to different chromosomes, turning the genome into an aneuploid mess. And this mess has consequences.

CIN can cause new mutations or make old ones have a stronger effect.  Eventually these mutations can affect genes that are important for keeping a cell’s growth in line.  Once these are compromised, a tumor cell is born. 

Since CIN is pretty common in yeast, we might be able to better understand it in cancer cells by studying it in yeast. The Hieter lab at the University of British Columbia has come up with a powerful screen to get yeast to confess why it CINs. 

A previous study from the group set the stage by finding a large group of mutants that have CIN phenotypes, implying that those genes are involved in keeping chromosome structure stable. In a new paper in G3: Genes, Genomes, Genetics, van Pel et al. uncovered the network of interactions among the genes in this set, using synthetic genetic array (SGA) technology. And they confirmed that the human homologs of some of these genes interact in the same way as in yeast, making them potential targets for cancer therapies.

The idea behind SGA studies is that if two proteins are involved in the same process, then a strain carrying mutations in both of their genes will be much worse off than a strain carrying either single mutation. In the worst case, the double mutant will be dead. This is known as a synthetic lethal interaction.

Yeast is a great model for doing these sorts of studies on a very large scale.  We can construct networks showing how lots of different genes interact, and most importantly, find the genes that are central to many interactions.   These “hubs” are likely to be the key players in those processes.

The researchers looked specifically for interactions between genes that are involved with CIN in yeast and are also similar to human cancer-related genes. They came up with various interaction hubs that will be interesting research subjects for a long time to come. In this study, they focused on one of these: genes involved with the DNA replication fork.

One of these in particular, CTF4, is a hub for both physical and genetic interactions. Unfortunately, Ctf4p doesn’t look like a good target for chemotherapy. It’s thought to act as a scaffold, and lacks any known activity that could potentially be inhibited by a drug. However, the interaction network around CTF4 that van Pel et al. uncovered suggests another way to target this hub. If a gene that interacts with CTF4 itself has a synthetic lethal interaction with another gene, and we could re-create the synthetic lethal phenotype in a cancer cell, we might be able to knock out the whole process. And that is just what they found in human cells.

First the authors identified a couple of human genes that were predicted from the yeast screen to be close to human CTF4 in the interaction network and to have a synthetic lethal interaction with each other. They then lowered the expression of one using small interfering RNA (siRNA), and reduced the activity of the other with a known inhibitor. Neither treatment alone had much effect, but combining them significantly reduced cell viability.

Since cancer cells frequently carry mutations in CIN genes, it should be possible to create a synthetic lethal interaction, guided by the yeast interaction network, where one partner is mutated in cancer cells (equivalent to using siRNA in this study) and the other partner is inhibited with a drug. Since it relies on a cancer-specific mutation, this approach has the potential to selectively target cancer cells while not disturbing normal cells, the ultimate goal for chemotherapy.

by Maria Costanzo, Ph.D., Senior Biocurator, SGD

Categories: Research Spotlight, Yeast and Human Disease

Tags: cancer, DNA replication, Saccharomyces cerevisiae, yeast model for human disease

SGD Download Files Temporarily Unavailable Monday March 25

March 20, 2013

The files at SGD’s Downloads site will be unavailable between 5-7 PM PDT (8-10 PM EDT) on Monday, March 25 (12-2 AM GST or 9-11 AM JST on Tuesday March 26) in order to maintain the server that hosts the site. Please plan ahead to download the files you need. YeastMine will be available during this time for custom downloads. We apologize for this inconvenience and thank you for your patience as we perform essential maintenance on SGD.

Categories: Maintenance

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