New & Noteworthy

Create, Analyze, Save: the Power of Gene Lists in YeastMine

May 30, 2014

If you love to make and analyze lists of genes, you will love YeastMine – you can use it to create all kinds of lists! For instance, use a YeastMine template to search for all genes associated with a given GO term or phenotype observable and save these genes as a list. Or, search for all genes that interact with your gene of interest and save that as a gene list.

What’s even more fun is that you can make lists from your lists! For instance, take the list of genes you found to be associated with a given GO term and plug it into a YeastMine query template to find all the genes that interact with your list of genes – then save those genes as a list. The possibilities are endless given the different types of queries you can perform using YeastMine! Who knows what biological connections you will uncover?

Lastly, save your lists for future use by creating a MyMine account – all you need to sign up is an email and a password.

You can find a link to YeastMine in the top right corner of most SGD pages (“YeastMine: Batch Analysis or Advanced Search”) or go to SGD’s purple main menu bar, click on “Analyze” and select “Gene Lists” to go straight to creating a List in YeastMine.

To see how simple it is to save your search results as a List in YeastMine, view this brief tutorial – YeastMine: Saving Search Results as a List. To view other great SGD tutorials, YeastMine and otherwise, visit and “Subscribe” to the Saccharomyces Genome Database Channel on YouTube.

Slipping Through Haldane’s Sieve

May 22, 2014

Imagine you are panning for gold in a river and there are two kinds of nuggets.  One type is naked gold while the other is gold hidden inside of normal rock.  Pretty easy to figure out which nuggets you’ll gather first!

Now imagine instead that the process of panning is a rough one that knocks the shell off of the second type of nugget revealing the gold inside.  Now there won’t be any difference between the two.  You will be just as likely to keep both types of nuggets.

The same sort of situation applies to new beneficial mutations in a changing environment.  Back in 1927, J. B. S. Haldane predicted that the more dominant a mutation, the more likely it was to help a diploid beast adapt to a new environment.  The naked gold was more likely to be taken over the covered gold.

Gerstein and coworkers show in a new study that at least in the yeast Saccharomyces cerevisiae, Haldane’s sieve (as it is called) may not always apply.  The process of adapting to a new environment can strip away the dominant older allele, revealing the recessive one.  Loss of heterozygosity (LOH) uncovers the hidden gold of the recessive phenotype.

The authors had previously identified haploid mutants that were able to survive in the presence of the fungicide nystatin.  They mated these mutants to create either heterozygotes or homozygous recessive mutants and compared these to wild-type diploids growing either in the presence or absence of nystatin. 

Gerstein and coworkers found a wide range of effects of these mutations in the absence of nystatin.  Sometimes heterozygotes grew better than either homozygote, sometimes homozygous recessive strains did best, and sometimes wild type grew best.   Phenotypes were all over the map.

The story was very different in the presence of nystatin where only the homozygous recessives managed to grow.  This appears to contradict Haldane’s sieve.  Here there were no dominant mutations that allowed for survival.

Gerstein and coworkers found that some heterozygote replicates started to grow after a prolonged lag period.  A closer look at the heterozygotes that grew showed that they had lost the dominant allele so that they could now show the recessive phenotype and survive.  LOH had broken Haldane’s sieve. 

The authors found that the lower the nystatin levels, the more likely a population was to break through Haldane’s sieve.  They postulate that the populations survive longer at lower levels of nystatin, which increases the chances that a LOH will happen.  It is a race between survival and eliminating the dominant allele that keeps them from growing. 

The next step was to determine if LOH was common enough that populations with a small percentage of heterozygotes could survive.  They found that even in populations where only 2% were heterozygotes, around 5% of the 96 replicate populations managed to lose an allele and grow.  So even at low levels, a recessive mutation can give a population the advantage it needs to adapt and survive.

Combining the awesome power of yeast genetics with cheap sequencing is allowing scientists to test fundamental models of genetics that will unearth how populations adapt and survive in new environments.  We are finding those nuggets of scientific knowledge that have remained hidden.

Now of course, not every diploid is as numerous or as genetically flexible as yeast.  Cows, chickens, lizards, and people may all still be slaves to Haldane’s sieve.  We will need more studies to see if our recessive treasures can be uncovered in time to save us. 

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

Possible Temporary Interruptions to SGD Service Sunday May 25

May 20, 2014

We are scheduling a maintenance window for SGD servers next Sunday, May 25 from 8:00 am to 5:00 pm PDT (11:00 am to 8:00 PM EDT; 3:00 pm to 11:00 pm GMT). During this window, some services may be temporarily unavailable for a short time. We will make every effort to minimize any downtime associated with this maintenance. We apologize for any inconvenience this may cause, and we thank you for your patience and understanding.

Yeast: A One Man Band for Finding New Drug Leads

May 15, 2014

Imagine you are in a band and the only instruments you have are guitars.  Yes, you can play some beautiful music, but there will be a whole lot of music that your band won’t be able to play. 

In some ways, finding chemical leads to develop into drugs is similar to an all guitar band.  The compounds in available libraries all tend to have a lot in common.  They are like a vast array of subtly different guitars.

In a new study, Klein and coworkers use synthetic biology to have the yeast Saccharomyces cerevisiae make more varied libraries on its own.  As an added bonus, the authors also use the yeast to assay the new leads.  Not only have they expanded the range of instruments available to your band, but they’ve also made it so you can play all the instruments.  You are now a one man band!

The first step in all of this is to have an assay that can easily pick out the important leads.  Klein and coworkers use a galactose inducible Brome Mosaic Virus (BMV) system they had previously developed.

In this system, if one of the viral genes is on, then it produces a fusion protein that includes the Ura3 protein.  When the URA3 gene is expressed, yeast die in the presence of 5-fluoroorotic acid (5-FOA).  So any yeast that can make a compound that can inhibit viral expression will survive in 5-FOA.

The next step in creating these in vivo libraries was to randomly assemble various biochemical pathways into yeast artificial chromosomes (YACs) and to transform them into yeast.  These pathways were chosen because they have yielded important compounds before or because they come from medically important beasts.  This work was described in detail in a previous paper.

Specifically, Klein and coworkers randomly combined cDNA genes from eight biochemical pathways into YACs and transformed them into the BMV replication yeast strain.  They found 74 compounds that allowed the yeast to survive in the presence of 5-FOA.  Of these, 28 had activity in a secondary BMV assay. 

A close look at the 74 compounds showed that by and large, most had characteristics that put them in the right ballpark to be useful leads.  They had low molecular weight and the right hydrophobicity, and were chemically complex. In addition, many could easily be improved chemically (this last point is called optimizability).  Most importantly, they were pretty unique from a drug lead point of view. 

Over 75% of the compounds resembled nothing in known libraries.  And the compounds were not similar to one another.  Klein and coworkers had created a wide range of instruments other than guitars.

Of course, keeping a yeast strain alive is hardly reason to look for a new drug.  But that isn’t all these compounds can do.  At least some of these leads show excellent activity against two viruses related to BMV, Dengue and hepatitis C, and one looks particularly promising. 

With a random combination of genes from a variety of biochemical pathways, yeast has been coaxed into synthesizing chemical leads that can target two medically relevant viruses.  Scientists should be able to use a similar approach to tackle other diseases.  All they need is a yeast strain with the right assay.

Yeast can make our bread rise, get us drunk, and now maybe cure us of disease.  Is there anything yeast can’t do?  Well, they still can’t play a guitar. 

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