MicroRNAs (miRNAs) are short nucleotide RNAs that negatively regulate gene expression at the post-transcriptional level. Partially double-stranded miRNAs interact with an RNA-induced silencing complex (RISC) where one strand termed the guide strand is selected, while the partner strand accumulates at a lower level and is presumed to be degraded. The miRNA-loaded RISC then binds to target mRNAs through imperfect complementary sequences located in the 3'UTR and causes translation inhibition. One miRNA may negatively regulate hundreds of target mRNAs. In this study, a pre-miR-155 mutant was used to elucidate that a single mutation creating a mismatch near the 3' end of miR-155 led to a shift in strand selection, causing an increased selection of miR-155(*) and a decreased selection of miR-155, thereby fine-tuning the translation of their target genes. Consequently, this resulted in a butterfly effect on global gene expression. Indeed, nearly half of the genes we analyzed in this study showed altered expression. Provided that over 800 miRNAs have been identified in humans to date, mutation of miRNA is expected to play a critical role in species evolution and individual diversity. (C) 2010 Elsevier Inc. All rights reserved.