RNA folding in Drosophila shows a distance effect for compensatory fitness interactions

Phylogenetic-comparative analysis was used to construct a secondary structure of Adh precursor messenger RNA (pre-mRNA) in Drosophila. The analysis revealed that the rate of coevolution of base-pairing residues decreases with their physical distance. This result is in qualitative agreement with a model of compensatory fitness interactions which assumes that mutations are individually deleterious but become harmless (neutral) in appropriate combinations. This model predicts that coupled mutations can become fixed in a population under mutation pressure and random genetic drift, when the mutations are closely linked. However, the rate of joint fixation drops as distance between sites increases and recombination breaks up favorable combinations. RNA secondary structure was also used to interpret patterns of linkage disequilibrium at Adh.