Insertions and deletions affect RNA-protein interactions through RNA secondary structure

RNA binding proteins are crucial for every step of the RNA life cycle and are major contributors to post-transcriptional regulation. Since binding of a protein competes with the internal base pairing of an RNA, the binding affinity of an RNA binding protein is sensitive to the overall RNA structure. We have previously shown that single nucleotide polymorphisms have the ability to significantly affect protein binding even 50 nucleotides away from the protein binding site through modifications to the RNA secondary structure. Here, we show that insertions and deletions in an RNA have an even stronger effect on protein-RNA interactions in their vicinity and that this effect grows with the length of the insertion or deletion. By studying the occurrence of natural insertion and deletion variants near protein binding sites, we also demonstrate that this effect appears to be under natural selection.