Abstract
MicroRNAs (miRNAs) control the abundance of the majority of the vertebrate transcriptome. The recognition sequences, or target sites, for bilaterian miRNAs are found predominantly in the 3′ untranslated regions (3′UTRs) of mRNAs, and are amongst the most highly conserved motifs within 3′UTRs. However, little is known regarding the evolutionary pressures that lead to loss and gain of such target sites. Here, we quantify the selective pressures that act upon miRNA target sites. Notably, selective pressure extends beyond deeply conserved binding sites to those that have undergone recent substitutions. Our approach reveals that even amongst ancient animal miRNAs, which exert the strongest selective pressures on 3′UTR sequences, there are striking differences in patterns of target site evolution between miRNAs. Considering only ancient animal miRNAs, we find three distinct miRNA groups, each exhibiting characteristic rates of target site gain and loss during mammalian evolution. The first group both loses and gains sites rarely. The second group shows selection only against site loss, with site gains occurring at a neutral rate, whereas the third loses and gains sites at neutral or above expected rates. Furthermore, mutations that alter the strength of existing target sites are disfavored. Applying our approach to individual transcripts reveals variation in the distribution of selective pressure across the transcriptome and between miRNAs, ranging from strong selection acting on a small subset of targets of some miRNAs, to weak selection on many targets for other miRNAs. miR-20 and miR-30, and many other miRNAs, exhibit broad, deeply conserved targeting, while several other comparably ancient miRNAs show a lack of selective constraint, and a small number, including mir-146, exhibit evidence of rapidly evolving target sites. Our approach adds valuable perspective on the evolution of miRNAs and their targets, and can also be applied to characterize other 3′UTR regulatory motifs.
Highlights
A fundamental property of biological systems is the regulation of gene expression
MiRNA target site evolution us to make inferences regarding how gene regulation originated and how it is changing over time
One gene regulatory system, which is widespread in mammals and other animals, relies upon regulators known as microRNAs, which recognize target sites within mRNAs, leading to post-transcriptional repression of the targeted mRNAs
Summary
Diverse systems have evolved to generate controlled gene expression patterns across cell types and in response to different environments. Nematodes, and flies have similar numbers of protein-coding genes, many of which are well conserved in their primary sequence [5], and yet the three clades exhibit marked phenotypic differences. Different species of cichlid fish that shared a common ancestor within the past one million years display a remarkably diversified set of morphological and behavioral traits, despite virtually identical genomes [6]. Changes in gene regulatory networks, including those that appear modest, underlie many of the most striking phenotypic and developmental differences between life forms, and the study of these changes is essential to a complete understanding of the evolution of biological systems
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