Polymorphic Polymorphic MicroRNA-Target Interactions: A Novel Source of Phenotypic Variation

Studying the muscular hypertrophy of Texel sheep by forward genetics, we have identified an A-to-G transition in the 3'UTR of the GDF8 gene that reveals an illegitimate target site for microRNAs miR-1 and miR-206 that are highly expressed in skeletal muscle. This causes the down-regulation of this muscle-specific chalone and hence contributes to the muscular hypertrophy of Texel sheep. We demonstrate that polymorphisms which alter the content of putative miRNA target sites are common in human and mice, and provide evidence that both conserved and nonconserved target sites are selectively constrained. We speculate that these polymorphisms might be important mediators of phenotypic variation including disease. To facilitate studies along those lines, we have constructed a database (www.patrocles.org) listing putative polymorphic microRNA-target interactions.