Molecular Mechanism for Hypertensive Renal Disease: Differential Regulation of Chromogranin A Expression at 3′-Untranslated Region Polymorphism C+87T by MicroRNA-107

A fundamental problem in biology is understanding how natural selection has shaped the evolution of gene regulation. Here we use SNP genotype data and techniques from population genetics to study an entire layer of short, cis-regulatory sites in the human genome. MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally repress mRNA through cis-regulatory sites in 3' UTRs. We show that negative selection in humans is stronger on computationally predicted conserved miRNA binding sites than on other conserved sequence motifs in 3' UTRs, thus providing independent support for the target prediction model and explicitly demonstrating the contribution of miRNAs to darwinian fitness. Our techniques extend to nonconserved miRNA binding sites, and we estimate that 30%-50% of these are functional when the mRNA and miRNA are endogenously coexpressed. As we show that polymorphisms in predicted miRNA binding sites are likely to be deleterious, they are candidates for causal variants of human disease. We believe that our approach can be extended to studying other classes of cis-regulatory sites.

MicroRNAs (miRNAs) are important regulators of eukaryotic gene expression. They have been implicated in a broad range of biological processes, and miRNA-related genetic alterations probably underlie more human diseases than currently appreciated. Several studies have identified genetic variants in miRNA target sites that are claimed to be associated with disorders ranging from Parkinson's disease to cancer. However, careful assessment of these studies indicates that very few provide a combination of rigorous genetic and functional evidence. We therefore suggest a set of concrete recommendations to guide future investigations. Specifically, we highlight the importance of unbiased association studies and follow-up functional experiments for providing a clearer picture of the extent to which microRNA target site variations are relevant in various human diseases.