The evolution of microRNA in primates

Thesis (Ph.D.)--University of Washington, 2016-06

MicroRNA play an important role in post-transcriptional regulation of most transcripts in the human genome, but their evolution within humans and across the primate lineage is largely uncharacterized. A particular miRNA can have one to thousands of messenger RNA targets, establishing the potential for a small change in sequence or overall miRNA structure to have profound phenotypic effects. However, the majority of non-human primate miRNA is predicted solely by homology to the human genome and lacks experimental validation. In the present study, we sequenced thirteen species representing a wide range of the primate phylogeny. Hundreds of miRNA were validated, and the number of species with experimentally validated miRNA was tripled. These species include a sister taxon to humans (bonobo) and basal primates (aye-aye, mouse lemur, galago). Consistent with previous studies, we found the seed region and mature miRNA to be highly conserved across primates, with overall structural conservation of the pre-miRNA hairpin. However, there were a number of interesting exceptions, including a seed shift due to structural changes in miR-501 and an increase in the number of miR-320 paralogs throughout primate evolution. We also identified 4521 SNVs within diverse human populations from the 1000 Genomes Project, again finding the seed region and mature miRNA to be most highly conserved, even among common variants. No variants exhibited population substructure and most were very rare, suggesting that purifying selection has been the driving force for human miRNA evolution. The conservation of human miRNA and the enriched regulation of neuronal processes among miRNA targets of non-conserved non-human primates illustrate the importance of investigating the miRNA of more distantly related primate species in order to learn more about human evolution.