Abstract

During microRNA (miRNA) biogenesis, one strand of a 21–22-nucleotide RNA duplex is preferentially selected for entry into a silencing complex. The other strand, known as the miRNA^* species, has typically been assumed to be a carrier strand. Here we show that, although Drosophila melanogaster miRNA^* species are less abundant than their partners, they are often present at physiologically relevant levels and can associate with Argonaute proteins. Comparative genomic analyses revealed that >40% of miRNA^* sequences resist nucleotide divergence across Drosophilid evolution, and at least half of these well-conserved miRNA^* species select for conserved 3' untranslated region seed matches well above background noise. Finally, we validated the inhibitory activity of miRNA^* species in both cultured cells and transgenic animals. These data broaden the reach of the miRNA regulatory network and suggest an important mechanism that diversifies miRNA function during evolution.

1. Sloan-Kettering Institute, Department of Developmental Biology, 521 Rockefeller Research Laboratories, 1275 York Ave, Box 252, New York, New York 10065, USA.

Correspondence to: Eric C Lai¹ e-mail: laie@mskcc.org

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