DMS and SHAPE: With differing results, which is correct?

If a base like Cytosine shows a different result for SHAPE mapping compared to DMS mapping, which mapping protocol is giving the more accurate result? Does the identity of the base matter? For example, does DMS give more accurate results for loops compared to helices?

The two don’t have to agree. In structured RNAs we often see A’s that are protected to SHAPE modification but accessible to DMS – in most of these cases, those A’s are known (from crystallography) to form non-canonical base pairs with other nucleotides. There’s some discussion of this in this very brief paper:

DMS vs. SHAPE paper

For these residues, they are not in ‘canonical’ secondary structure.

It is also possible in some cases for noise to make DMS and SHAPE disagree… we’ll hopefully be able to resolve these problems as the experimental pipeline switches to Illumina sequencing instead of capillary electrophoresis.