GoKawiilOur genomes are full of mutations that have the potential to damage our health or even kill us. Yet most of them rarely cause problems. Why?
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It’s partly thanks to a family of proteins that mask, or ‘buffer’, the ill effects that these mutations would otherwise unleash. This buffering might help to explain why gene variants cause disease in some people but seem to have limited or no impact on others. It could also underlie how some cancer cells and pathogens threaten their hosts and evade drugs. And it enables genetic variation to accumulate in populations, providing a potential resource for future evolution.
Researchers have known for decades that one of the most important factors in mutational buffering is a protein called HSP90 and its family of other HSP proteins. Now, biologists are examining the roles of these proteins in more detail than they ever could before, owing to advances in techniques such as cell screening and genetic editing, as well as the availability of large genomic data sets and extensive health records.
Advances in the past two decades or so have “shifted our view on HSP90 buffering as a theoretical idea to one with immediate and important practical applications, especially in the clinic”, says geneticist Georgios Karras at the University of Texas MD Anderson Cancer Center in Houston. HSP90, for instance, might mediate the risks of breast cancer linked to the BRCA1 gene in some individuals. Some drugs that target buffering proteins are already being developed.
Researchers have long suspected that these proteins might influence the course of evolution, and results from the past several years have strengthened that notion. By ensuring that organisms can thrive despite harbouring risky gene mutations, buffering proteins build up a pool of variation that can be released in the face of environmental stress, triggering the rapid emergence of new adaptations. In this way, says Karras, HSP90 has probably “shaped adaptive evolution of life on Earth”.
Folding assistants
In the 1950s, biologist Conrad Waddington wanted to study how an animal’s environment affected its physical traits. He kept some fruit fly pupae at 40 °C for a few hours — a much higher temperature than the pupae would normally experience. Waddington saw that this heat-shock treatment had induced new wing shapes in some of the resulting flies. By selectively breeding flies with abnormal wings, the mutant phenotypes eventually appeared even without the heat treatment1. They had become genetically fixed. This suggested that the genetic variation underlying these phenotypes was already present in fly populations but was somehow hidden until the heat treatment revealed it.
Waddington’s work puzzled his contemporaries. It didn’t seem to fit with the prevailing view of how genes give rise to inherited traits. Independent work in the following decades identified genes that were switched on by heat exposure; the proteins produced by these genes became known as heat-shock proteins (HSPs).
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