microRNAs in the Same Clusters Evolve to Coordinately Regulate Functionally Related Genes

Mol Biol Evol. 2016 Sep;33(9):2232-47. doi: 10.1093/molbev/msw089. Epub 2016 Apr 28.


MicroRNAs (miRNAs) are endogenously expressed small noncoding RNAs. The genomic locations of animal miRNAs are significantly clustered in discrete loci. We found duplication and de novo formation were important mechanisms to create miRNA clusters and the clustered miRNAs tend to be evolutionarily conserved. We proposed a "functional co-adaptation" model to explain how clustering helps newly emerged miRNAs survive and develop functions. We presented evidence that abundance of miRNAs in the same clusters were highly correlated and those miRNAs exerted cooperative repressive effects on target genes in human tissues. By transfecting miRNAs into human and fly cells and extensively profiling the transcriptome alteration with deep-sequencing, we further demonstrated the functional co-adaptation between new and old miRNAs in the miR-17-92 cluster. Our population genomic analysis suggest that positive Darwinian selection might be the driving force underlying the formation and evolution of miRNA clustering. Our model provided novel insights into mechanisms and evolutionary significance of miRNA clustering.

Keywords: coordinated regulation; evolution; functional co-adaptation; mRNA-Seq; miR-17–92 cluster.; miRNA clusters; natural selection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Evolution
  • Cluster Analysis
  • Conserved Sequence
  • Evolution, Molecular
  • Gene Expression Profiling / methods
  • Gene Expression Regulation*
  • Genomics / methods
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • MicroRNAs / genetics*
  • Multigene Family*
  • Selection, Genetic
  • Sequence Analysis, RNA / methods
  • Transcriptome


  • MicroRNAs