New & Noteworthy

The Benefits of Sex

March 3, 2016

It is a good thing for lion-kind that these cubs weren’t budded off their mom asexually! Image from Stephanie Cornell via Pinterest.

While you doggedly swipe right and left or wait night after night at that club, you may be wondering whether it is all worth it. Biologists have been wondering something similar.

Now they haven’t been wondering about the value of sex…since everything from amoebas to zebras has sex, it must be pretty important. No, the hard part has been figuring out why it is so beneficial.

On balance it can seem that the minuses of disease risk and passing on only half of your DNA outweighs the benefits of the combining two individual sets of DNA for some brand new combination. A new study by McDonald and coworkers in Nature using our old friend S. cerevisiae provides compelling evidence for a couple of ways that sex is good for a species.

First it is a way of combining individual beneficial mutations into a single individual. Now rather than having a couple of well adapted individuals battling for supremacy, the mutations can merge into one super beast that can outcompete everyone else.

This benefit, recombination speeds adaptation by eliminating competition among beneficial mutations, had been predicted and goes by the name of the Fisher-Muller effect. But this is the first time scientists have actually seen it playing out at the DNA level.

The second big benefit of sex is freeing good mutations from a bad genetic background. Now the beneficial mutation is not weighed down by other negative mutations. It’s like finally getting rid of that concrete block tied around your ankle.

Yeast is an ideal system for studying the benefits of sex because it can happily exist as a sexual or asexual creature. This means that researchers can directly compare the two in the same experiment. Which is just what McDonald and coworkers did.

They followed 6 sexual and 12 asexual populations through about 1000 generations of adaptation. The only difference between the asexual and sexual populations was, as you might have guessed, sex.

The sexual populations included 11 bouts of sex. In other words, every 90 generations or so, an ‘alpha’ cell would swipe left and find an ‘a’ cell to hook up with.

As expected and has been seen before, the sexual populations were much better adapted to their environment than were the asexual populations. Sex is clearly a good thing! The next step was to tally up the mutations in each population to try to figure out why.

What McDonald and coworkers found was that there wasn’t a lot of difference in the mutations that crop up in each. Over time, both groups had about the same number and ratio of intergenic, synonymous, and nonsynonymous mutations.

The big difference between the asexual and the sexual populations was in the mutations that became fixed. In the sexual group, most mutations were weeded out over time. In their experiment, 78% of mutations became fixed in the asexual population while only 16% hung around in the sexual population.

Even the birds and the bees do it! Image from

Sheer numbers wasn’t the only difference between the two either. The kinds of mutations that became fixed differed significantly in both as well.

In the asexual population, each of the three kinds of mutations fixed at around the same rate. Around 75-80% of intergenic, synonymous and nonsynonymous mutations became established in this population.

It was a different story in the sexual population. Here, 22% of the nonsynonymous, 11% of the intergenic and none of the synonymous mutations became fixed. It seems like only mutations that make a difference end up getting selected for.

Further analysis revealed two big reasons why the two populations differed. First, good mutations ended up getting stuck with other bad mutations in the asexual population. This blunted the positive effects of the beneficial mutation.

And second, the various good mutations tended to be spread out among different groups in the asexual population. The end result was that instead of working together, these groups battled each other for supremacy resulting in some beneficial mutations being lost.

So no need to wonder anymore about the benefits of sex to a species. It is a strong purifier, weeding out unimportant or damaging mutations and a powerful aggregator, squirrelling all the good ones into one group. No wonder most every beast does it!

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

Join SGD at The Allied Genetics Conference

February 29, 2016

TAGC 2016 imageSGD will be attending The Allied Genetics Conference (TAGC) in Orlando, Florida, July 13–17, 2016! For the first time ever, the meetings of the yeast, C. elegans, ciliate, Drosophila, mouse, and zebrafish model organism communities will be united under one roof, along with a new meeting on population, evolutionary, and quantitative genetics.

Submit your abstracts now! Abstract submission will be open until March 23, 2016. If you want GREAT science and access to the leaders of the field, then TAGC is the place for you. SGD will be there, will you?

Not Quite The Same

February 24, 2016

From a first glace you might think these images are the same but they aren’t. Just like the gene expression pattern of a yeast auxotroph grown in complete media is not the same as that of the wild type strain. Image from Wikimedia Commons.

Imagine a world where you either make your own bread from scratch or have it delivered to your doorstep. Not much of a difference, right? Either way you’re eating bread.

Except of course that the two are pretty different. Having your bread delivered frees up time to do other things.

It turns out that something similar may be going on in our old friend, Saccharomyces cerevisiae. According to a new study in Nature Microbiology by Alam and coworkers, a yeast able to make its own amino acids or nucleobases works very differently than one that can’t but is supplied all the nutrients it can use.

This is important for yeast studies because these sorts of auxotrophic markers are used all the time. It means researchers need to be very careful about comparing a wild type yeast strain with a yeast strain deleted for, say, URA3, but grown in the presence of plenty of uracil. The two are not equivalent.

And the study may even have implications for other folks as well. For example, cancer cells have many mutations, some of which can be in metabolic genes. These mutations may affect how these cancers respond to drug treatment.

This all might not matter much if the effects were small. But they weren’t in this study. The changes were profound.

Alam and coworkers compared 16 different strains that were identical except that four different metabolic genes were deleted in various combinations. These genes included HIS3, LEU2, URA3 and MET15 (also known as MET17).

Using mRNA sequencing, they found that 5,011 out of 5,923 transcripts were affected in one strain or the other. This is 85% of the coding genome of yeast!

While not all of these changes were huge, 573 of them differed by 2-fold or more. In other words, around 10% of the genome is significantly affected when a yeast cell is provided a nutrient instead of having to make it itself. Not surprisingly, the affected genes were enriched for those involved in metabolic activity and enzymatic function.

The authors next looked at some publically available gene expression experiments that used auxotrophs in the same BY4741 background. These studies primarily looked at the how the knocking out of a specific gene affected global gene expression. The vast majority of deleted genes were not metabolic.

Alam and coworkers found that a sizeable minority of changes overlapped with the ones they saw with deleting HIS3, LEU2, URA3 or MET15. In other words, on average, at least 18% of the changes in the genes identified in these studies were not due to the gene deletion they were studying. They were instead due to the deletion of a “housekeeping” metabolic gene.

This all might be less of a big deal if the affected genes were always the same. Then you could just be on the lookout for these genes when using a specific auxotroph.

Not all replacements are equal to the original. Image from

Unfortunately, it isn’t so easy. Different combinations of deleted metabolic genes yield different changes in gene expression patterns with very little overlap.

So, for example, when the authors compared a his3 deletion strain to one deleted for both HIS3 and URA3, a very different set of genes was affected. And these were different from a strain deleted for HIS3 and MET15, and so on. Looking at all the possible combinations confirmed that universal gene targets were rare.

The bottom line from these experiments is that researchers need to be very careful about the strains they compare because they may not be as equivalent as they think. Just because the older Star Trek films and the newer ones have a Spock, that doesn’t mean the half Vulcan is the same in both. Just ask Uhura.

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

Unlocking Chromatin

February 10, 2016

Transcription factors need to break through a number of locks in the right order to get to their prize. Image from Petar Milošević via Creative Commons.

In Die Hard, Hans Gruber and associates need to break through seven locks in the right order on a safe to get to bearer bonds worth 640 million dollars. Of course the hero John McClane foils the plot and beats the villains.

Nothing so exciting in yeast, but some genes are nearly as hard to turn on as that safe was to open. One of the most stubborn is the HO gene. It requires three locks or gates be opened in the right order to start making the HO endonuclease.

A new study in GENETICS by Yarrington and coworkers shows that the second lock for HO is a set of nucleosomes that blocks the binding of the transcription activator SBF. When they rejiggered this promoter so that these nucleosomes were removed, the HO gene needed fewer steps to get activated.

It is as if Hans Gruber and his gang only had five or six locks to get through to open their safe. And the 7th, hardest one was removed.

The HO gene is usually turned on in three sequential steps. First the Swi5p activator binds to a region called URS1, which recruits coactivators that then remodel the chromatin at the left half of URS2 (URS2-L). This allows SBF to bind its previously hidden binding sites which then remodels the chromatin again. Now a second set of SBF sites is revealed in the right half of URS2 (URS2-R).

These authors set out to provide direct proof that nucleosome positioning over URS2-L is the key to the second lock. They did this by making a set of chimeric promoters between HO and CLN2.

Both of these promoters are activated by SBF. A key difference between the two is that the CLN2 promoter, like 95% of yeast promoters, is in a nucleosome depleted region (NDR).

The idea then is to make an HO promoter in which the usual URS2-L is replaced with the NDR region of CLN2. If the nucleosomes matter over URS2-L, then this construct should be activated in two instead of three steps.

Or, to put it another way, Swi5p binding to URS1, the first lock, will no longer be needed to open the second lock. HO activation will now be Swi5p independent. This is what the authors found.

Given that it switches a yeast cell’s mating type, it isn’t surprising that the HO gene is under such lock and key. Image from Wikimedia Commons.

When they looked at their chimeric protein that lacked nucleosomes over URS2-L, they found that using a strain deleted for SWI5 had very little effect on activity. There was only around a 2-fold difference in activity with this construct in the wild type and SWI5-deleted strains. This is very different than the wild type HO promoter where there was around a 15-fold difference between the two strains.

The authors then did an additional experiment where they took their chimeric reporter and mutated the nucleosome depleted region such that nucleosomes could bind there. This construct was now more Swi5p-dependent: there was around a 5-fold difference in activity between the wild type and SWI5 deletion strains. They had at least partially rebuilt that second lock.

Yarrington and coworkers continued with ChIP experiments to confirm that their chimeric construct was indeed depleted for nucleosomes, as well as other experiments to tease out more subtle details about the regulation.

Given that it switches a yeast cell’s mating type, it isn’t surprising that the HO gene is under such lock and key. The yeast cell wants to make sure it only turns on when needed. Just as the Nakatomi Corporation wanted to make sure only the right people could get to that fortune in bearer bonds.

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

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