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Inferring the evolutionary history of primate microRNA binding sites: overcoming motif counting biases.

ABSTRACT: The first microRNAs (miRNAs) were identified as essential, conserved regulators of gene expression, targeting the same genes across nearly all bilaterians. However, there are also prominent examples of conserved miRNAs whose functions appear to have shifted dramatically, sometimes over very brief periods of evolutionary time. To determine whether the functions of conserved miRNAs are stable or dynamic over evolutionary time scales, we have here defined the neutral turnover rates of short sequence motifs in predicted primate 3'-UTRs. We find that commonly used approaches to quantify motif turnover rates, which use a presence/absence scoring in extant lineages to infer ancestral states, are inherently biased to infer the accumulation of new motifs, leading to the false inference of continually increasing regulatory complexity over time. Using a maximum likelihood approach to reconstruct individual ancestral nucleotides, we observe that binding sites of conserved miRNAs in fact have roughly equal numbers of gain and loss events relative to ancestral states and turnover extremely slowly relative to nearly identical permutations of the same motif. Contrary to case studies showing examples of functional turnover, our systematic study of miRNA binding sites suggests that in primates, the regulatory roles of conserved miRNAs are strongly conserved. Our revised methodology may be used to quantify the mechanism by which regulatory networks evolve.

SUBMITTER: Simkin AT

PROVIDER: S-EPMC4069616 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Inferring the evolutionary history of primate microRNA binding sites: overcoming motif counting biases.

Simkin Alfred T AT Bailey Jeffrey A JA Gao Fen-Biao FB Jensen Jeffrey D JD

Molecular biology and evolution 20140409 7

The first microRNAs (miRNAs) were identified as essential, conserved regulators of gene expression, targeting the same genes across nearly all bilaterians. However, there are also prominent examples of conserved miRNAs whose functions appear to have shifted dramatically, sometimes over very brief periods of evolutionary time. To determine whether the functions of conserved miRNAs are stable or dynamic over evolutionary time scales, we have here defined the neutral turnover rates of short sequenc ...[more]

PMID: 24723422

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Project description: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.

Dataset Information

Inferring the evolutionary history of primate microRNA binding sites: overcoming motif counting biases.

Publications

Inferring the evolutionary history of primate microRNA binding sites: overcoming motif counting biases.

Similar Datasets

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