Off-target effects

A key feature ofsiRNAsis that they inhibit genes in a highly specific manner. Indeed, the initial description of these RNAs demonstrated that alternation of a single base pair was sufficient to disruptgene silencing. For many subsequent studies with siRNAs this specificity was shown to hold true. A number of more recent studies have suggested that there are situations where mismatches between the siRNA and target sequence can be tolerated. This observation has raised the concern that siRNAs may have effects on genes that are not considered targets, so called off-target effects. This concern has been addressed by a number of groups that have examined genome-wide changes in gene expression following the introduction of siRNAs. Some of these studies found that a number of genes unrelated to the target are changed in expression, mostly by a factor of twofold. These off-target effects have been correlated with the concentration of siRNAs, as well as similarities between the off-target transcripts and the 5' ends of siRNAs. It seems plausible on the basis of recent work that the decreased off-target mRNA levels are the consequence of siRNAs adopting miRNA-like properties, resulting in slightly decreased levels of mRNAs, possibly through alterations in mRNA stability. The exact mechanism remains to be determined.

More about RNAi off-target effects inPubMed.

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