Abstract
Post-transcriptional regulation by miRNAs is a widespread and highly conserved phenomenon in metazoans, with several hundreds to thousands of conserved binding sites for each miRNA, and up to two thirds of all genes under miRNA regulation. At the same time, the effect of miRNA regulation on mRNA and protein levels is usually quite modest and associated phenotypes are often weak or subtle. This has given rise to the notion that the highly interconnected miRNA regulatory network exerts its function less through any individual link and more via collective effects that lead to a functional interdependence of network links. We present a Bayesian framework to quantify conservation of miRNA target sites using vertebrate whole-genome alignments. The increased statistical power of our phylogenetic model allows detection of evolutionary correlation in the conservation patterns of site pairs. Such correlations could result from collective functions in the regulatory network. For instance, co-conservation of target site pairs supports a selective benefit of combinatorial regulation by multiple miRNAs. We find that some miRNA families are under pronounced co-targeting constraints, indicating a high connectivity in the regulatory network, while others appear to function in a more isolated way. By analyzing coordinated targeting of different curated gene sets, we observe distinct evolutionary signatures for protein complexes and signaling pathways that could reflect differences in control strategies. Our method is easily scalable to analyze upcoming larger data sets, and readily adaptable to detect high-level selective constraints between other genomic loci. We thus provide a proof-of-principle method to understand regulatory networks from an evolutionary perspective.
Highlights
In the last two decades, micro-RNAs have emerged as key players in post-transcriptional gene regulation [1,2]
Quantitative, versatile, and scalable Bayesian strategy to evaluate preferential conservation of a target site and evolutionary correlations between two target sites
We develop a background model for the conservation of Kmers along the vertebrate lineage, and use it to evaluate the conservation of real miRNA target sites above this background (Fig. 1C)
Summary
In the last two decades, micro-RNAs (miRNAs) have emerged as key players in post-transcriptional gene regulation [1,2]. A conserved seed match is by far the most informative indicator of a regulatory interaction, but many other determinants of miRNA targeting are known, such as the sequence context in the 39UTR, the accessibility of the site within the mRNA secondary structure, and the proximity to the stop codon or the polyadenylation site [9] These general trends were first inferred using indirect evidence from transcriptome and proteome profiling [10,11], and were recently corroborated by experimental advances allowing transcriptome-wide mapping of Argonaute binding sites [12,13,14,15,16], non-canonical sites without perfect complementarity in the seed region abound [15,16,17,18]. We aimed to develop refined species- and gene-specific background models, by averaging the Kmer conservation statistics over all Kmers in a given 39UTR and over 39UTRs with similar conservation patterns
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