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Novikova et al., 2012;

Sauvageau et al., 2013). While the functional importance of lncRNAs such as Xist is well accepted, more general roles are still controversial, especially in light of low primary sequence conservation through evolution (Graur et al., 2013;

Nitsche et al., 2015). A conserved RNA sec- ondary structure can occur despite weak conservation of the pri- mary sequence. For example, riboswitches (regulatory RNAs with exquisite control over metabolism in bacteria) typically have nucleic acid sequence identities of only 50%C65% but sec- ondary structures conserved across thousands of sequences (Mandal and Breaker, 2004;

Nawrocki et al., 2015;

Roth and Breaker, 2009). Likewise, the U2 and U4 spliceosomal RNAs, 5S rRNA, and group I introns have low sequence identities but highly conserved structures (Nawrocki et al., 2015). In such cases of low sequence identity, sequence-based search algo- rithms (e.g., BLAST) are not generally productive;

however, a strategy that aligns syntenic sequences according to chemically probed structures has proved successful for identifying ribos- witch RNAs (Cheah et al., 2007;

Weinberg et al., 2009). While few in vivo chemical probing studies on riboswitches have been performed, nearly every in vitro chemical probing-derived ribosw........