Chaperon proteins do more than... chaperon

The full human genome was typed for the first time in 2003. Ever since, there has been a "hunt" for mutations and, more in general, associations between genotypes and phenotypes. As I have pointed out multiple times on this blog, things have turned out more complicated than originally anticipated: what happens between DNA and proteins (what we could consider the "end" product) is still very much a "black box" in which epigenetic changes and RNA editing can completely turn around the outcome. Furthermore, the interaction between genes and mutated loci can either increase or decrease the likelihood of certain phenotypes, given the genotype.

Take molecular chaperones, for example. These are proteins that assist the folding and unfolding of other macromolecules. They are typically involved in protein folding, but they also assist the assembly of nucleosomes from folded histones and DNA in the nucleus (see this earlier post on chromatin) and thus, by changing the topology of the nucleus, they play an important role in regulating gene expression.

A study published in the last issue of Science [1] looks at the role of chaperon proteins in compensating for deleterious mutations in Caenorhabditis elegans. Casanueva et al. found that worms with higher expression of protective chaperon genes were more resistant to deleterious mutations: worms with a potentially deadly mutation received a mild heat stress when still larvae. The heat stress promoted the expression of protective chaperon genes, and in some of the worms this prevented the deleterious misfolding of proteins, resulting in a 35% increase in chance of survival.

"We subjected animals to a transient heat shock as larvae to induce a stress response, allowed them to develop to adults, and examined the proportion of individuals affected by late-acting mutations. When a mutation was chaperone-dependent, a mild environmental challenge stimulated a reduction in penetrance."

Paradoxically, they also found that individuals with higher chaperon expression reproduced less. Why, if the higher expression seems advantageous and protective? Casanueva et al. hypothesize that the net effect is to maintain a heterogeneous population in levels of expression, and this is more advantageous to the survival of the population than homogeneous levels of gene expression. In other words, what is advantageous to the individual is not necessarily advantageous to the species.

From the paper abstract:

"The induced mutation buffering varies across isogenic individuals because of interindividual differences in stress signaling. This variation has important consequences in wild-type animals, producing some individuals with higher stress resistance but lower reproductive fitness and other individuals with lower stress resistance and higher reproductive fitness. This may be beneficial in an unpredictable environment, acting as a “bet-hedging” strategy to diversify risk. These results illustrate how transient environmental stimuli can induce protection against mutations, how environmental responses can underlie variable mutation buffering, and how a fitness trade-off may make variation in stress signaling advantageous."

Of course, it's not clear how this could apply to humans. However, it does prompt caution when treating a person's full genome as a key to disease risks. We are still far from unraveling the complete interactions between genome, epigenome, and proteome, and, as I've often said before, Mother Nature has made us far more complex than any of our models can predict.

[1] Casanueva, M., Burga, A., & Lehner, B. (2011). Fitness Trade-Offs and Environmentally Induced Mutation Buffering in Isogenic C. elegans Science, 335 (6064), 82-85 DOI: 10.1126/science.1213491

Photo: it's not what it looks like! This is eggs, water and vegetable oil all mixed in a blue bowl to make brownies. Seriously. You just set the bowl under a lamp and suddenly it behaves like a mirror. Eventually the mix turned into brownies, but not before my daughter and I had a little fun shooting pictures.