RNAi stronger than mutants


I was wondering if there are instances in literature of when RNAi gives a stronger phenotype than a mutant (null). I guess the only way to explain that would
be compensation or off-target effects.


There are a number of instances of inviable mutants that are partially maternally rescued by gene product from their heterozygous mothers, for which the RNAi effect is stronger than the homozygous phenotype. I realize, it’s not quite what you were asking for - technically the maternally rescued animals aren’t null, even if the allele is a molecular null.

Off target effects could produce a stronger effect with RNAi, especially if the target gene was part of a superfamily and one ended up depleting multiple members of that family.

Another interesting possibility is that reducing transcript levels in a tissue-specific manner could produce compensatory effects that result in stronger phenotypes than null mutants. Such an explanation was proposed for the stronger RNAi effect produced by knocking down an activin receptor in the Drosophila ring gland relative to a putative null. Since C. elegans neurons are refractory to RNAi, such a situation could arise in the course of an RNAi experiment. I think that off-target effects might be more likely, but it’s an interesting explanation to consider.