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Posts Tagged ‘drosophila’

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Once again Hsp90 changes how we think about evolution

In Uncategorized on July 14, 2008 at 1:37 pm


post to news.thinkgene.com

Hsp90 and it’s possible role in evolution (as a capacitor for rapid change), I have covered extensively in the  5 post series for JustScience week 08 (Revolution Evolution, Presenting….Hsp90, How can chaperones act in evolution, Evidence for Hsp90 involvement in rapid evolution of new traits and Hsp90 to end controversies in evolution theory). Recently I found this thorough review on the subject from which I would like to share the essentials (review written by Roberta L Millstein at University of California, Davis):

Recent work on the heat-shock protein Hsp90 by Rutherford and Lindquist …. has been included among the pieces of evidence taken to show the essential role of developmental processes in evolution;

To recap, the theory is that heat shock proteins can hide genetic variation until a stressful environment exposes them to allow rapid change (evolution) of morphology and subsequently, traits.

Hsp90 acts as a buffer against phenotypic variation, allowing genotypic variation to build. When the buffering capacity of Hsp90 is altered (e.g., in nature, by mutation or environmental stress), the genetic variation is “revealed,” manifesting itself as phenotypic variation.

The theory is backed up by genetic experiments on Drosophila and Arabidopsis. Results from this research on Hsp90 lends support to channeling and “hopeful monster” theory and as such, follows the more controversial line of evolution-thinking. The review sums up many of the controversial sides of conclusions from the Hsp90 research:

This phenomenon raises questions about the genetic variation before and after what I will call a “revelation event”: Is it neutral, nearly neutral, or non-neutral (i.e., strongly deleterious or strongly advantageous)? Moreover, what kinds of evolutionary processes do we take to be at work?

My goal with the previous posts on Hsp90 was to show that the data lends sufficient support to alter and revise how we think about evolution. It seems this is the goal of the review as well.

The primary goal of this paper is to illuminate the alternative scenarios and the processes operating in each. At the end, I raise the possibility of a synthesis between evo-devo and nearly neutral evolution.

Evolution I strongly believe, is not entirely and exclusively driven by a random (and slow) constant mutation rate, but rather controlled by a number of additional mechanisms to ensure that an organism can evolve rapidly. To me, this is not controversial at all, – it does not overturn any Darwinian principles, but serves as an extention to explain the speed of evolution that has sometimes baffled us. Nevertheless, conclusions drawn from Hsp90 research remains controversial to many evolutionists, and Millstein sums it up with:

I find it somewhat ironic that people who are otherwise unorthodox in their thinking with respect to evolution are so orthodox when it comes to adaptationism. After all, as the late Gould argued, nonadaptive approaches were left out of the evolutionary synthesis (Gould 1983) just as developmental processes were (Gould 2002).

Which to me, a molecular biologist gone amateur evolutionist, is a good ending note. Reviews like this, one can only hope, will lend credibility to alternative thoughts on mechanisms of Darwinian evolution. Which is surely needed to fully understand the beauty and complexity of the molecular mechanisms that shapes our world.

Note: the review I have linked to is open access, but apparantly only a draft, the final version is available here, but isn’t open access (shame on you Biological Theory and MIT press Journals).

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Hsp90 to end controversies in evolution theory (final chapter, blogging in Just Science 08)

In Uncategorized on February 8, 2008 at 9:42 am

Previous posts have shown Hsp90 to be a molecular buffer allowing rapid morphological changes in times of stress. As will be discussed below, such a buffering function supports the evolutionary theories of punctuated equilibria, hopeful monsters and canalization.

So…, this last post will end with the final conclusions based on the arguments presented in the previous 4 posts. But, first….Two fundamental questions:

1. Even if Hsp90 can promote rapid changes in phenotype (appearance) how is this change retained (fixed) for future generations ?

This fixation has been demonstrated to occur (see Sangster TA et al.), and the traits become independent of Hsp90. The exact mechanism(s) however remains to be elucidated.

Nevertheless, temporarily compromising Hsp90 function (either by drugs or by temperature rise) is sufficient for fixing new traits. Simulations seem to show that knocking out the genes for key proteins (not necessarily heat shock proteins) lead to increased phenotypic diversity, and thus the underlying cause may be genetic fixation. However, interplay between epigenetic and genetic mechanisms has been suggested and been backed up by experiments. Thus fixation probably happens through yet to determined genetic as well as epigenetic mechanisms, or a combination of both. A model for epigenetic fixation is given in the thumbnail below:

Epigenetic evolution through Hsp90

Models for genetic fixation follows the theory of canalization with Hsp90 functioning as the Waddington’s widget (see Semin Cell Dev Biol. 2003 Oct;14(5):301-10). This is discussed further under the next bulletpoint, the second question…..

2. Does these aspects of Hsp90-function fit into current models of evolution ?

Yes, although some of these theories are controversial. First we have the idea of punctuated equilibrium and hopeful monsters discussed in my previous post. To expand on these ideas let’s also include the theory of canalization. Canalization explains punctuated equilibrium by referring to an organisms buffering capacity (to counter the potential deleterious effects of mutations). The theory was put forward by C. H. Waddington more than 50 years ago, but is still controversial it seems. Hsp90 is a molecular explanation of the canalization concept in that organisms with different genotypes express the same phenotype until times of stress. There are also indications that other heat shock proteins or other “signaling hub”-proteins or even miRNA can serve such buffering functions (see references within this review).

Taken together, these controversial evolutionary theories and the experimental evidence on Hsp90 supports one another, and a paradigm shift in evolutionary biology is in place. Darwins theories are correct up to the point of gradual and constant evolution of traits. Evolution instead, occurs in bursts. This series of blogposts have conveyed the molecular evidence for such punctuated equlibria and canalization, which comes from studies on the molecular chaperone Hsp90. I hope I have enlightened and convinced at least some evolution biologists into believing that Darwins theories can be expanded to include these (no longer controversial) theories.

There are however, a lot to work out in terms of the underlying molecular mechanisms for Hsp90 (and/or other buffering bioactive molecules ?) in canalization. To end this blogpost-series I will therefore quote the closing remarks from Salathia N and Queitsch C‘s review in 2007:

“Clearly, organisms have succeeded in integrating multiple canalization mechanisms into robust wild-type phenotypes which can respond appropriately to environmental perturbations and evolve new shapes and functions over time. Now it is up to us to determine how molecules as diverse as a molecular chaperone, chromatin remodeling proteins, and the RNAi machinery interact coherently to achieve such synergy, a truly fascinating and worthy field of future inquiry.”

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Evidence for Hsp90 involvement in rapid evolution of new traits (chapter IV, blogging in Just Science 08)

In Uncategorized on February 7, 2008 at 10:39 am

Previous posts have attempted to demonstrate that there is a potential role for (Heat Shock) proteins that mask mutations, to enable rapid evolutionary changes. The Hsp90 protein has been presented and the basic problems one face to explain bursts in evolution have been outlined. Now the time has come to show real examples of Hsp90 influencing the evolution of traits.

The following are very short summaries of key papers. For details, please see the referenced papers.

1. Hsp90 and Cancer

In 1993 Yang Xu and Susan Lindquist showed that Hsp90 associates with v-src and inhibits its activity in an concentration-dependent manner. Hsp90 was not merely an on and off switch for v-src, but exhibited transient inhibition, dependent on intracellular concentration of Hsp90. This was a clue to understanding Hsp90’s role in cancer (as well as in evolution). After this, many cancer-related proteins have been identified that interact with Hsp90 (see table).

Table from a review in Nature 2005 by Whitesell and Lindquisthsp90-table-2005-review.jpg

The mechanism one speculates, is similar at the molecular level, to the mechanisms postulated for morphological change. Hsp90 stabilizes the otherwise unstable oncogenic proteins, to aid in tumor growth in an environment hostile to tumor development. In other words: the heat shock proteins protects the oncogenic cells from stress. When the tumor cells subsequently attain further mutations and protein alterations, inherent to oncogenic growth, the heat shock proteins are unable to stabilize all of the altered proteins and the tumor can progress into accelerated growth and/or metastasis. The role of Hsp90 in cancer development has been widely accepted and inhibitors of Hsp90 activity is currently undergoing clinical trials for cancer treatments.

2. Drosophila

The key paper on Hsp90 and Drosophila evolution is the Rutherford and Lindquist paper in Nature 1998. This paper has been mentioned on several previous posts here on SciPhu and also in the introductory Just Science post. Again, the take home message is that reducing levels of Hsp90-activity leads to changes in phenotype. The reason for such dramatic effects is probably that Hsp90 stabilizes proteins that are key elements in intracellular signaling pathways. Often these are kinases, phosphatases or transcription factors, see this table for full list. The common feature of these affected proteins is that they regulate the activity of other proteins downstream in the signaling cascade. Thus, changes in the activity of one master protein acts on the stability and function of many other “executive” proteins ultimately resulting in massive changes. The phenomenon has further been elucidated in other species……….

3. Yeast

In yeast, a reduction in Hsp90 levels potentiates drug resistance and this resistance has multigenic determinants working through Hsp90. Hsp90 thus helps yeast evolve to counter the stressful effect of the drug. Interestingly, this effect is diminished by temperature rise. Increasing the stress (by adding heat) therefore, titrates Hsp90 away from the drug-resistance and makes the yeast vulnerable again (could this effect explain why fever has developed ?).

4. Arabidopsis

Evidence for the same mechanisms occurring in plants comes mainly from two publications on Arabidopsis thaliana (Queitsch C et al. and Sangster TA et al.). These images from the latter publication show the extensive morphological changes seen in the plants.

journalpone0000648g002.png
Figure 2. Similar morphological phenotypes of seedlings with reduced HSP90 function by RNAi or pharmacological means (GDA). (a) and (b): purple pigment accumulation; (c) and (d): organ number defect; (e) and (f): narrowly-shaped deformed true leaves; (g) and (h): twisted rosettes; (i) and (j): lobed cotyledon. RNAi plants are T3 generation with from line RNAi-A3. Size bar 2 mm for b and g–i, 1 mm for a, c–f, and 3 mm for normal phenotype. (b) and (f) originally published in [5].

These effects can also be induced by increasing the temperature. Demonstrating the generality in the stress response. Since the genetics of these plants is easier to trace in these plants than in Drosophila or Yeast, the evidence for buffering genetic changes is even more clear-cut in this organism.

An excellent illustration to summarize Hsp90-buffering comes from Sangster TA et al.:

Hsp90-buffering

In the last post I will present published models on how Hsp90 can act in evolution, – welcome back for the last post in Just Science 08, tomorrow.