New & Noteworthy

Mixing Mitochondria Makes Magic

May 31, 2018

In the Harry Potter universe, there are two materials that make up a wand: the wood, which comes from trees like cedar and holly, and the core, which is a magical substance such as the feather of a phoenix or a unicorn hair.

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A variety of wizarding wands. From Flickr.

Every wand has unique properties that depend mainly on the combination of its wood and core. Different wood-core pairings give different characteristics that can either antagonize or synergize with the wizard using it. When a wand meets up with its ideal owner, it will begin to learn from and teach its human partner. Such auspicious pairings can continuously improve the wizard’s spell-casting, helping the wizard perform better and better under ever more varied circumstances. However, a poor pairing between a wand and a wizard can be devastating, enfeebling the wizard’s magic or even causing it to backfire.

And just like wizards and wands, it turns out that mitochondrial DNA and nuclear DNA in a cell need to be properly paired to perform the “magic” of running a cell in the most efficient way.

Mitochondria are dynamic structures inside eukaryotic cells that provide much of the energy to keep a cell humming along.

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A mitochondrion. These sub-cellular organelles produce much of the energy for a cell in the form of ATP. From Wikimedia Commons.

Mitochondria contain their own DNA, encoding genes necessary for the organelle to do its work. Although mitochondrial DNA is physically separate from nuclear DNA, it turns out that the two need to work together if the cell is to make functioning mitochondria.

Like the wand-wizard pairing in Harry Potter’s world, the combination of a specific mitochondrial genome (the wand) with a particular nuclear genome (the wizard) is important for making a healthy mitochondrion. Some mitochondrial-nuclear combinations work well and others not so much, but not a lot is known about where different mitochondrial DNAs come from and how they end up paired with their favored nuclear genomes.

Knowing more about this may help us understand how mitochondrial genomes evolve during interspecific hybridizations, such as in lager beer yeast and certain other fermentation yeasts.

A new study in GENETICS from Wolters et al. shows that when S. cerevisiae yeast cells go through the mating process, there is often mixing of mitochondrial genomes to give new combinations of mitochondrial genes — almost as if lots of new wood-core combinations of wands were being created.

How do these new mitochondrial combinations arise? When two haploid yeast cells mate, they merge to form a single diploid cell that contains mitochondria from both of its parents. Sometimes, these mitochondria exchange pieces of DNA, mixing-and-matching genes in a process known as mitochondrial recombination.

The authors found that a surprising proportion of mated yeast cells (~40%) had recombinant mitochondrial DNA. And in many cases, the recombined mitochondrial genomes work even better with the nuclear genome to make a super healthy cell. Often these optimal pairings allowed the cells to develop new powers, tolerating higher temperatures and more oxygen-stressed conditions than the original parent cells — in other words, the cell has found its optimal “wand”!

But other pairing combinations were inauspicious, giving sickly or dead mitochondria that can harm the cell, especially when it is growing under stressful conditions. For instance, when the authors swapped the mitochondrial-nuclear pairing for two different but very fit cell types, these new pairings gave unhealthy cells, meaning that the original fit cells had already found their perfect “wand”.

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Harry Potter first meeting his perfectly-paired wand. From harrypotter.wikia.com.

So just like when Harry Potter was in Ollivander’s wand shop and finally found his holly-phoenix feather wand and felt unified with its amazing magic, yeast cells can acquire new super powers when their nuclear and mitochondrial genomes are perfectly paired!

by Barbara Dunn, Ph.D. and Kevin MacPherson, M.S.

…and we wish a fond farewell to Barry Starr, Ph.D. who has left the Stanford Department of Genetics for new horizons. We miss you Barry and wish you well!

Categories: Research Spotlight

Tags: recombination , mitochondria , environmental stress

Species Can’t Risk the New Coke

January 29, 2015


Genome organization may protect key genes from the ravages of increased mutation rate during meiosis:

Back in 1985, Coca Cola decided to completely rejigger the flavor of their flagship soft drink, calling it the New Coke. This radical change to the product was a colossal failure. Toying with such an essential part of a key product was simply too risky a move. If only they had learned from our favorite beast, Saccharomyces cerevisiae.

If only Coke had protected its essential recipe as well as yeast protects its essential genes! Image via Wikimedia Commons

In a new study in PLOS Genetics, Rattray and coworkers show that the mutation rate is higher during meiosis in yeast because of the double-strand breaks associated with recombination. This makes sense, because any new mutations need to be passed on to the next generation for evolution to happen, and germ cells are made by meiosis. But their results also bring up the possibility that key genes might be protected from too many mutations by being in recombination cold spots. Unlike the Coca Cola company, yeast (and everything else) may protect essential genes from radical change.

Previous work in the Strathern lab had suggested that when double strand breaks (DSBs) in the DNA are repaired, one result is an increased mutation rate in the vicinity. The major culprit responsible for the mutations appeared to be DNA polymerase zeta (Rev3p and Rev7p).

To test whether the same is true for the DSBs that happen during the first meiotic prophase, Rattray and coworkers created a strain that contained the CAN1 gene linked to the HIS3 gene. The idea is that mutants in the CAN1 gene can be identified as they will be resistant to canavanine. The HIS3 gene is included as a way to rule out yeast that have become canavanine resistant through a loss of the CAN1 gene. So the authors were looking for strains that were both resistant to canavanine and could grow in the absence of histidine.

The first things the authors found was that the mutation rate during meiosis was indeed increased as compared to mitosis in diploids. For example, when the reporter cassette was inserted into the BUD5 gene, the mitotic mutation rate was 5.7 X 10-8 while the meiotic mutation rate was 3.7 X 10-7, a difference of around 6.5 fold.

This effect was dependent on the DSBs associated with recombination, since the increased mutation rate wasn’t seen in a spo11 mutant; the SPO11 gene is required for these breaks. Using a rev3 mutant, the authors could also conclude that at least half of the increased mutation rate is due to DNA polymerase zeta. This all strongly suggests that the act of recombination increases the local mutation rate.

If recombination is associated with the mutation rate, then areas on the genome that recombine more frequently should have a higher rate of mutation during meiosis. And they do. The authors inserted their cassette into a known recombination hotspot between the BUD23 and the ARE1 genes and saw a meiotic mutation rate of 1.77 X 10-6  as compared to a rate of 4.9 X 10-7 when inserted into a recombination coldspot. This 3.6 fold increase provides additional evidence that recombination is an important factor in meiotic recombination.

This may be more than just an unavoidable side effect of recombination. It could be that yeast and perhaps other beasts end up with their genes arrayed in such a way as to protect important genes by placing them in recombination dead zones.

And perhaps genes where lots of variation is tolerated or even helpful are placed in active recombination areas. In keeping with this, recent studies have shown that essential S. cerevisiae genes tend to be located in recombination cold spots, and that this arrangement is conserved in other yeasts.

It is too early to tell yet how pervasive this sort of gene placement is.  But if this turns out to be a good way to protect essential genes, Coca Cola should definitely have left the Coke formula in a part of its genome with little or no recombination. Mutating that set of instructions was as disastrous as mutating an essential gene!

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

Categories: Research Spotlight

Tags: recombination , evolution , Saccharomyces cerevisiae , meiosis

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