NMR Studies of HAR1 RNA Secondary Structures Reveal Conformational Dynamics in the Human RNA

Comparative genomics has shown that noncoding RNAs can display substantial differences between humans and chimpanzees. The human accelerated region 1 (HAR1) is a section in the human genome that exhibits the most strongly accelerated rate of nucleotide substitution in relation to the chimpanzee genome. It is associated with higher cognitive functions in human brains. The HAR1 region of the HAR1F gene is transcribed into a 118 nt noncoding RNA. We provide experimental data to validate available secondary structure models of chimpanzee and human HAR1 RNA by utilizing CD and NMR spectroscopy and applying a divide-and-conquer strategy. The mutations lead to more dynamic secondary and tertiary structure in the human HAR1 RNA, presumably as part of its function. We have also determined NMR solution structures of helix H1 as the most conserved part of the chimpanzee and human HAR1 RNAs. Helix H1 contains a GAA asymmetric internal loop, the structure of which had not been solved previously. 37 nt chimpanzee and human RNA fragments (c37 and h37 RNAs) differ in a single base pair. h37 RNA folds into a slightly more stable and rigid structure than c37 RNA. Both NMR structures show structural heterogeneity of the residues corresponding to the GAA loop.