A novel method of RNA secondary structure prediction based on a comparison
of nucleotide sequences is described. This method correctly predicts nearly
all evolutionarily conserved secondary structures of five different RNAs:
tRNA, 5S rRNA, bacterial ribonuclease P (RNase Pi RNA, eukaryotic small sub
unit rRNA, and the 3' untranslated region (UTR) of the Drosophila bicoid (b
cd) mRNA. Furthermore, covariations occurring in the helices of these conse
rved RNA structures are analyzed. Two physical parameters are found to be i
mportant determinants of the evolution of compensator! mutations: the lengt
h of a helix and the distance between base-pairing nucleotides. For the hel
ices of bcd 3' UTR mRNA and RNase P RNA, a positive correlation between the
rate of compensatory evolution and helix length is found. The analysis of
Drosophila bcd 3' UTR mRNA further revealed that the rate of compensatory e
volution decreases with the physical distance between base-pairing residues
. This result is in qualitative agreement with Kimura's model of compensato
ry fitness interactions, which assumes that mutations occurring in RNA heli
ces are individually deleterious but become neutral in appropriate combinat
ions.