New & Noteworthy

Another Small Victory for Lamarck

July 29, 2015


Yeast gives us an example of an adaptation that is positively Lamarckian! Image of Jean Baptiste de Lamarck via Wikimedia Commons

Examples of various ways that the environment affects gene expression have become so commonplace that new examples don’t make much of a splash anymore. It is as if Lamarck and Darwin had never argued about how natural selection works.

The main reason we aren’t surprised anymore is that we have a pretty good handle on how most of these changes are happening. Something in our environment causes chemical groups to be added or removed from our DNA and/or its associated proteins, causing a change in gene expression. These kinds of epigenetic changes happen a lot and are now seen as the norm.

What doesn’t happen much at all is that the underlying DNA gets changed in a predictable way to change gene expression in response to something in the environment. Which is why a recent study in PNAS by Jack and coworkers makes you stand up and take notice.

In this study the researchers provide evidence that suggests that yeast will expand the number of copies of its rDNA locus to match the level of nutrients in the environment (presumably to make more ribosomes to take advantage of all those nutrients). The yeast is responding to the environment by changing the content of its genome rather than just changing how it is used.

This is big. It is almost as if Lamarck was right about some part of natural selection. Oh wait, that’s exactly what it is! 

What makes this so cool is that it suggests that natural selection doesn’t necessarily just happen when a random genetic variant wins out in a population. Sometimes the environment itself can induce the winning genome change–and these aren’t just epigenetic changes. (Go Lamarck!)

Jack and coworkers focused on the rDNA locus of the yeast Saccharomyces cerevisiae. This is a fairly fluid part of the yeast genome that consists of multiple copies of the 35S and 5S pre-rRNA genes. The average yeast cell has around 180 copies of this locus and there is a normal range of 150-200 per cell. If a yeast somehow ends up with 80 or fewer copies, it quickly increases the number back to that golden 150-200 range via a Fob1 dependent mechanism.

The authors created a strain of yeast that lacked Fob1 and had only 35 tandem repeats in its rDNA region. This strain, rDNA35, could not expand its rDNA unless Fob1 was added back. They now had a strain in which they could test what affected rDNA expansion, by transforming the strain with a plasmid expressing Fob1 and growing the transformants under different conditions.

The most surprising experiment was the final one of the paper. The authors grew the rDNA35 strain in either 2% or 0.5% glucose and found that rDNA amplification was slowed significantly in low glucose. The authors interpret this to mean that the genome change, the expansion of rDNA, is dependent on nutrient availability. A signaling pathway is able to adjust the rate of rDNA expansion.

Yeast will, of course, grow more slowly at low levels of glucose than they will at higher levels. But the authors were able to show that slow growth was not the reason for the slowed expansion of rDNA at low glucose. They were able to separate the two effects by overexpressing Pnc1, a nicotinamidase.

Overexpression of Pnc1 led to a decreased rate of copy number increase even at the higher glucose levels without affecting growth rate. So rDNA expansion can be separated from slow growth under the right conditions. And as you’ll see below, Pnc1 makes perfect sense given how at least part of nutrient level-dependent rDNA amplification works.

In looking for factors that might affect the rate of rDNA expansion, Jack and coworkers focused on the TOR signaling pathway, since previous work had suggested that it might be important in this process and it is known to respond to nutrient availability. The authors confirmed it was a key player by showing that rapamycin, a TOR inhibitor, kept the rDNA35 strain from expanding its rDNA in the presence of FOB1.

Again they ran into the problem of disentangling cell growth and the rDNA expansion, as rapamycin slows cell growth. The next set of experiments showed that the lack of expansion was almost certainly not due to the slower growth rate.

It is known that rapamycin affects histone deacetylases (HDACs) including Sir2. Jack and coworkers found that nicotinamide, a Sir2 inhibitor, increased the rate of expansion of rDNA without affecting growth rate. So rDNA amplification was not dependent on growth rate.

Which brings us back to Pnc1, that enzyme that cleaves nicotinamide! Presumably endogenous levels of nicotinamide are able to inhibit Sir2 and so encourage the rDNA expansion. Overexpressing Pnc1 releases Sir2 which can then impede the expansion of rDNA.

While that was a bit complicated, the idea is simple and potentially profound. Yeast can sense the level of nutrients in their environment at least partially through the TOR signaling pathway and adjust the actual content of their genome accordingly.

The involvement of nicotinamide in this regulatory process makes this result even cooler, as it has important roles in aging and cellular metabolism from yeast to man. For example, it plays a key role in the life extending properties of caloric restriction in yeast and possibly in more complicated eukaryotes as well. (Click here for a fascinating look at NAD, a compound that contains nicotinamide.)

So, in the presence of low nutrient levels, yeast expand their rDNA much more slowly than they would at higher nutrient levels. Yeast can tailor its genome in response to its environment so it can better utilize that environment.

This work raises the fascinating possibility that this process might even happen at genomic regions other than the rDNA locus. Yeast still has plenty of surprises in store—including giving a Lamarck a little boost.

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

Categories: Research Spotlight

Tags: ribosomal DNA amplification , Saccharomyces cerevisiae , nicotinamide , environmental response

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