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Evolution by weakening: how mutations work together

Evolution by weakening: how mutations work together

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Published by Steve Matheson

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Published by: Steve Matheson on Aug 08, 2011
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08/10/2011

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Molecular evolution: improve a protein by weakening it
 by Stephen F. MathesonOriginally published onQuintessence of Dust
 
,August 2011
In the cartoon version of evolution that is often employed by critics of the theory, a new protein (B)can arise from an ancestral version (A) by stepwise evolution only if each of the intermediatesbetween A and B are functional in some way (or at least not harmful). This sounds reasonableenough, and it's a good starting point for basic evolutionary reasoning.But that simple version can lead one to believe that only those mutations that help a protein, or leaveit mostly the same, can be proposed as intermediates in some postulated evolutionary trajectory.There are several reasons why that is a misleading simplication – there are in fact many ways inwhich a mutant gene or protein that seems to be partially disabled might nevertheless persist in apopulation or lineage. Here are two possibilities:1. The partially disabled protein might be benecial precisely because it's partially disabled. In otherwords, sometimes it can be valuable to turn down a protein's function.2. The effects of the disabling mutations might be masked, partially or completely, by othermutations in the protein or its functional partners. In other words, some mutations can be crippling inone setting but not in another.In work just published by
at the University of Oregon, reconstruction of the likelyevolutionary trajectory of a protein family (i.e., the steps that were probably followed during anevolutionary change) points to both of those explanations, and illustrates the increasing power of experimental analyses in molecular evolution.The main focus of the Thornton lab is the
. By combining phylogenetic inference (i.e., examiningmolecular "pedigrees" to infer the nature of an ancestral protein) and hard-core biochemistry andbiophysics, Thornton and his colleagues can identify the likely ancestral proteins that gave rise to themodern receptors, then "resurrect" them in the lab and study their properties.The reconstructions of receptor pedigrees have led to the following basic history of the receptors.1. An ancestral receptor, present about 450 million years ago in a vertebrate, responded to twodifferent kinds of steroid hormone at high sensitivity. This means that the receptor wasn't veryselective, but it was sensitive, so it didn't take a lot of hormone to get a response.2. The gene encoding that receptor was duplicated at some point, and the two resulting genesdiverged to become specialized. One receptor (we'll just call it the MR) retained many of theancestral features: low selectivity, high sensitivity. The other receptor (the glucocorticoid receptor,which we'll call the GR) became selective for one type of hormone (glucocorticoids, the kind of steroid that includes cortisol) but also became a lot less sensitive. And that is the current situation inall vertebrates, as far as we know.
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Previous studies in Thornton's lab outlined a likely trajectory through which the different receptorsprobably changed specicity. But the interesting loss of sensitivity remained unexplained.
 
, Sean Michael Carroll and his colleagues in the Thornton labtackle this question, uncovering an interesting type of genetic interaction that is a hot topic inevolutionary biology right now. Their paper is titled "
."The authors already knew that all known GRs have low sensitivity. That includes GRs from the maintypes of vertebrates: tetrapods like us, bony sh like salmon and piranhas, and non-bony sh (calledcartilaginous sh) like sharks and rays. They suspected that this meant that hormone sensitivity wasrst reduced in the common ancestor of all of those animals. To test this hypothesis, they rst neededto examine GRs from animals throughout the vertebrate family tree, so they could infer the nature of the GR in the common ancestor. You might want to take a few minutes to examine the simple familytree of the receptors and of the various animals, presented in
and reproduced below.So the authors obtained GR gene sequences from four different species of shark (representatives of the cartilaginous shes), then created the proteins in the lab and asked whether low sensitivity was auniversal feature of cartilaginous shes.
illustrates the simple answer: yes, it is.Each of the points on the graph represents the amount of hormone necessary to activate the receptor.The different colors represent different kinds of hormone, and we can focus on just one, let's say thedark blue. The different animals are indicated across the bottom; on the left are ancestral receptors,inferred from looking at the family tree, and on the right are each of ve cartilaginous shes: a skate(previously known) and the four new contestants (the sharks). Notice that the amount of hormone
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needed to activate the receptor goes up with each step in the left-hand box, and is even higher ineach animal in the right-hand box. It takes more hormone to activate the receptor – it became lesssensitive, and seems to have acquired this characteristic a long time ago.How long ago, and how would did the authors infer that? Well, they created a postulatedreconstruction of the ancestral receptor – the receptor in the common ancestor – by combiningknowledge of rates of change in proteins with the new knowledge gained by looking at four newanimals (the sharks). The graph in Figure 2 shows the hormone sensitivity of this new reconstruction(it's version 1.1) compared to an older reconstruction based on just one cartilaginous sh (that wasversion 1.0). The new "resurrected" ancestral receptor (AncGR1.1) has much lower sensitivity thanits much more ancient ancestor (AncCR), the one with high sensitivity but no selectivity. So it seemsthat the change in sensitivity happened after the duplication event but before any of the various kindsof vertebrates diverged, something less than 450 million years ago.But
how
did the change come about? Let's look back at the family tree in Figure 1 to get oriented.The grandparent of all the receptors is called AncCR and it was sensitive but not selective. After theduplication, there were two parents, if you will: the MR parent which we're not discussing, and theGR parent, called the AncGR. AncGR, the parent of 
all 
the GRs, had reduced sensitivity. Carroll andcolleagues addressed the
how
question by rst looking at the types of changes that occurred betweenthe grandparent and the parent.There were 36 changes that accrued during that time. The authors used some straightforwardreasoning to narrow the list of suspects down to six. In other words, six different changes in theprotein, together or separately, were likely to account for the change in sensitivity. They went intothe lab and resurrected each of those mutant proteins, and measured their sensitivity. And their datatell a very interesting story, presented as a graph in
.The gray bar is the grandparent. The yellow bar is the parent. (The scale is logarithmic, so thechange in sensitivity from grandparent to parent is at least 100-fold.) The other bars represent thesensitivity of some of the mutations that must have generated the low-sensitivity parent. So, the rstwhite bar is mutant 43. (The number represents a particular location of the mutation, but we're notinterested in that here.) That mutation drops sensitivity to near-parental levels. The next bar ismutant 116. It also reduces sensitivity to the parental level. Sounds good. But wait:
both
of thosemutations are present in the parent. What happens when you put them together? Disaster. Look at thenext white bar: it's the combination of 43 and 116, and the receptor is effectively dead. As theauthors put it in the abstract, "the degenerative effect of these two mutations is extremely strong."
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