Project description:Like protein coding genes, loci that produce microRNAs (miRNAs) are generally considered to be under purifying selection, consistent with miRNA polymorphisms being able to cause disease. Nevertheless, it has been hypothesized that variation in miRNA genes may contribute to phenotypic diversity. Here we demonstrate that a naturally occurring polymorphism in the MIR164A gene interacts epistatically with an unlinked locus to affect leaf shape and shoot architecture in Arabidopsis thaliana. A single-base pair substitution in the miRNA complementary sequence alters the stability of the miRNA:miRNA* duplex. It thereby interferes with processing of the precursor and greatly reduces miRNA accumulation. We demonstrate that this is not a rare exception, but that natural strains of Arabidopsis thaliana harbor dozens of similar polymorphisms that affect processing of a wide range of miRNA precursors. Our results suggest that natural variation in miRNA processability due to cis mutations is a common contributor to phenotypic variation in plants.