Preferential regulation of duplicated genes by microRNAs in mammals
1 Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
2 Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, ON, M5S 3E1, Canada
3 Banting and Best Department of Medical Research, University of Toronto, 160 College Street, Toronto, ON, M5S 3E1, Canada
Genome Biology 2008, 9:R132 doi:10.1186/gb-2008-9-8-r132Published: 26 August 2008
Although recent advances have been made in identifying and analyzing instances of microRNA-mediated gene regulation, it remains unclear by what mechanisms attenuation of transcript expression through microRNAs becomes an integral part of post-transcriptional modification, and it is even less clear to what extent this process occurs for mammalian gene duplicates (paralogs). Specifically, while mammalian paralogs are known to overcome their initial complete functional redundancy through variation in regulation and expression, the potential involvement of microRNAs in this process has not been investigated.
We comprehensively investigated the impact of microRNA-mediated post-transcriptional regulation on duplicated genes in human and mouse. Using predicted targets derived from several analysis methods, we report the following observations: microRNA targets are significantly enriched for duplicate genes, implying their roles in the differential regulation of paralogs; on average, duplicate microRNA target genes have longer 3' untranslated regions than singleton targets, and are regulated by more microRNA species, suggesting a more sophisticated mode of regulation; ancient duplicates were more likely to be regulated by microRNAs and, on average, have greater expression divergence than recent duplicates; and ancient duplicate genes share fewer ancestral microRNA regulators, and recent duplicate genes share more common regulating microRNAs.
Collectively, these results demonstrate that microRNAs comprise an important element in evolving the regulatory patterns of mammalian paralogs. We further present an evolutionary model in which microRNAs not only adjust imbalanced dosage effects created by gene duplication, but also help maintain long-term buffering of the phenotypic consequences of gene deletion or ablation.