Natural Variation in Gene Expression Modulates the Severity of Mutant Phenotypes.

Many mutations cause genetic disorders. However, two people inheriting the same mutation often have different severity of symptoms, and this is partly genetic. The effects of genetic background on mutant phenotypes are poorly understood, but predicting them is critical for personalized medicine. To study this phenomenon comprehensively and systematically, we used RNAi to compare loss-of-function phenotypes for ∼1,400 genes in two isolates of C. elegans and find that ∼20% of genes differ in the severity of phenotypes in these two genetic backgrounds. Crucially, this effect of genetic background on the severity of both RNAi and mutant phenotypes can be predicted from variation in the expression levels of the affected gene. This is also true in mammalian cells, suggesting it is a general property of genetic networks. We suggest that differences in the manifestation of mutant phenotypes between individuals are largely the result of natural variation in gene expression.

Acute Effects of Drugs on Caenorhabditis elegans Movement Reveal Complex Responses and Plasticity.

Many drugs act very rapidly - they can turn on or off their targets within minutes in a whole animal. What are the acute effects of drug treatment and how does an animal respond to these? We developed a simple assay to measure the acute effects of drugs on C. elegans movement and examined the effects of a range of compounds including neuroactive drugs, toxins, environmental stresses and novel compounds on worm movement over a time period of 3 hr. We found a wide variety of acute responses. Many compounds cause rapid paralysis which may be permanent or followed by one or more recovery phases. The recoveries are not the result of some generic stress response but are specific to the drug e.g., recovery from paralysis due to a neuroactive drug requires neurotransmitter pathways whereas recovery from a metabolic inhibitor requires metabolic changes. Finally, we also find that acute responses can vary greatly across development and that there is extensive natural variation in acute responses. In summary, acute responses are sensitive probes of the ability of biological networks to respond to drug treatment and these responses can reveal the action of unexplored pathways.