The evolution of microRNA-regulation in duplicated genes facilitates expression divergence

Background: The evolution of microRNA regulation in metazoans is a mysterious process: MicroRNA sequences are highly conserved among distal organisms, but on the other hand, there is no evident conservation of their targets. Results: We study this extensive rewiring of the microRNA regulatory network by analyzing the evolutionary trajectories of duplicated genes in D. melanogatser. We find that in general microRNA-targeted genes tend to avoid gene duplication. However, in cases where gene duplication is evident, we find that the gene that displays high divergence from the ancestral gene at the sequence level is also likely to be associated in an opposing manner with the microRNA regulatory system – if the ancestral gene is a miRNA target then the divergent gene tends not to be, and vice versa. Conclusions: This suggests that miRNAs not only have a role in conferring expression robustness, as was suggested by previous works, but are also an accessible tool in evolving expression divergence. Background MicroRNAs (miRNA) are short RNA molecules that inhibit protein synthesis by targeting mRNA transcripts [1]. Intriguingly, while miRNAs typically exhibit very high sequence conservation even among evolutionarily distant species, their mRNA targets are specific to each species, with as little overlap as can be expected by chance [2-5]. This portrays the evolution of regulation by miRNAs as a mysterious process, in which the regulatory elements are kept under strong stabilizing selection, while the elements which they regulate are free to diverge. The lack of target conservation may indicate a high turnover of cis-elements in the 3' UTR of mRNA transcripts, similar to what has been suggested for transcription factor binding sites (TFBSs) in gene promoter sequences [6-12]. Several works have argued that the latter may, in fact, have little effect on phenotype, as changes can be compensatory, and even when they are not, mRNA expression patterns may often change by way of neutral drift [13, 14]. Could the same be true for miRNA