Perspective in the evolution of human microRNAs: Copy number expansion and acquisition of target gene specialization

Abstract

A novel class of small, noncoding RNAs called microRNAs (miRNAs) was recently identified, and up to 20%-30% of human genes are said to be regulated by the members of this class of RNA. miRNAs regulate their target genes by imperfect binding to the 3′ untranslated region (UTR) of the gene transcript, and computational predictions of the binding between miRNAs and target gene transcripts have been performed in order to determine which genes are regulated by these RNAs. Phylogenetic analysis has also been used as a powerful tool to predict miRNA target genes. Much emphasis has therefore been placed on studying the phylogenetic conservation and evolution of this novel type of gene regulator, although there still is much that is not known. Here, we propose a hypothesis of how human miRNAs optimized their gene regulation by adjusting their transcript levels, and how they evolved through specific selection of their target genes. We analyzed the correlation between the conservation of miRNAs among species and three features: the number of transcripts, the formation of duplicates, and the number of target genes. The number of miRNA transcripts and the formation of duplicates increased as the conservation rate increased. In contrast, the number of target genes decreased as the conservation rate increased. Therefore, we propose that miRNAs gradually gain an ability to regulate specific target genes when such regulation has a positive effect on the organism. As its pool of target genes is refined, the ability of an miRNA to regulate the genes may be stabilized by an increase in the miRNA transcript number and the formation of duplicates.