New & Noteworthy
April 1, 2013
When you think of a chaperone, you probably think of a strict adult at the prom who keeps a tight rein on the kids’ behavior. Well, in nature, a chaperone sometimes has to do the opposite to help new genes form more quickly. Sometimes the chaperone has to give the gene a longer leash to explore lots of different possibilities.
See, in theory, it is pretty easy to make a new gene. A cell accidentally makes an extra copy of an existing gene and this gene is then free to mutate into something new. A few mutations later and you have a new gene.
Turns out this is probably trickier than it sounds. First off, having an extra copy of a gene can cause problems. And second, getting to a new function is no walk in the park either. It usually takes a few sequential mutations to get there and, with proteins being such persnickety things, many of the intermediates along the way end up being unstable.
One way a cell might deal with these issues is to bring in a chaperone that lets the gene tolerate more mutations. Chaperones are proteins that help stabilize other proteins, often under trying conditions like high temperature. They coddle the protein and keep it stable so that it can still do its job. In addition, chaperones can also cause a protein to relocate to different parts of the cell.
So the idea is that if a duplicated gene gains a mutation that lets its protein interact with a chaperone, the protein may get more stability from that interaction or may be rerouted to where it won’t do any harm. Because the chaperone buffers the possible harmful effects for the cell, the gene is free to explore more different intermediates on the way to its new function.
A new study out in GENETICS by Lachowiec and coworkers lends support to this “capacitor hypothesis.” The authors used both Arabidopsis and Saccharomyces cerevisiae to show that genes whose proteins interact with the chaperone Hsp90 evolved more quickly than closely related genes that did not. This strongly supports the idea that chaperones can encourage new functions in duplicated genes.
The authors first looked at a couple of closely related transcription factors from Arabidopsis, BES1 and BZR1. Using a specific inhibitor of HSP90 called geldanamycin (GdA), they were able to show that BES1 was a client of HSP90 but BZR1 was not. They then created a phylogenetic tree of Arabidopsis BZR/BEH gene family and, by determining the ratio of non-synonymous to synonymous changes, found that BES1 had a higher rate of mutation. One explanation is that the stabilizing/relocalizing influence of HSP90 allowed BES1 to tolerate more mutations.
This result was an excellent first step in showing that the capacitor hypothesis may be true in some cases, but it is limited by being based on a single pair of proteins. To broaden their findings, Lachowiec and coworkers took advantage of the vast knowledge about Hsp90 interactions in Saccharomyces cerevisiae to look at many more genes.
At first this didn’t work out that well. The authors looked at a data set of yeast proteins that interacted with Hsp90 (encoded in yeast by the HSP82 and HSC82 genes) and, after removing any co-chaperones from the set, found no difference in the rate of evolution between those proteins that interacted with Hsp90 and those that did not. But as the authors note, this isn’t surprising as so many other factors play a role in the rate of evolution too.
To refine their analysis, they mimicked their BES1/BZR1 study and focused on pairs of closely related proteins where one interacted with Hsp90 and the other did not. They found that proteins that interacted with Hsp90 had a “longer branch length” than did their close relatives that did not interact. In other words, Hsp90 appeared to help along the formation of a new gene.
The authors then went back to Arabidopsis and showed that BZR and BES1 were found in distinct but overlapping parts of the cell. This lends credence to the idea that chaperones cause proteins to localize to different parts of the cell.
So it looks like an important function of chaperones may be to shepherd new gene formation. They are more like a 1960’s version of a chaperone…they let duplicated genes make lots of mistakes on their way to discovering who they really are.
by D. Barry Starr, Ph.D., Director of Outreach Activities, Stanford Genetics