Evolutionary Divergence of Brain-specific Precursor miRNAs Drives Efficient Processing and Production of Mature miRNAs in Human.

The hallmark of human evolution encompasses the dramatic increase in brain size and complexity. The intricate interplays of micro-RNAs (miRNAs) and their target genes are indispensable in brain development. Sequence divergence in distinct structural regions of Brain-specific precursor miRNAs (pre-miRNAs) and its consequence in the production of corresponding mature miRNAs in human are unknown. To address these questions, first we classified miRNAs into three categories based on tissue expression: Brain-specific (expressed exclusively in brain), Non-brain (expressed in Non-brain tissues) and Common (expressed in all tissues) and compared the sequence divergence of different structural regions (basal segment, lower and upper stem, internal and terminal loop) of categorized pre-miRNAs across human, non-human primates and rodents. Our analysis revealed that unpaired regions of Brain-specific pre-miRNAs in human bear traces of relatively high rate of evolutionary divergence compared to those in other species. Cross-tissue expression analysis unveiled the higher expression of the Brain-specific miRNAs in human compared to other species. Intriguingly, in human brain, expression levels of these miRNAs superseded the levels of the ubiquitously expressed "Common-miRNAs". Further analysis revealed that presence of certain motif and nucleotide preference in the Brain-specific pre-miRNAs may favor DROSHA and DICER to ameliorate miRNA processing. The higher processing efficiency of human Brain-specific miRNAs was reflected as an elevated production of corresponding mature miRNAs in the human brain. Finally, re-construction of gene-regulatory network uncovers different pathways driven by Brain-specific miRNAs that may contribute to the development of brain in human.