RNA Folding in Drosophila Shows a Distance Compensatory Fitness Interactions Effect for Wolfgang

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. T HE question of whether evolution can proceed on a surface of selected values from one adapted peak to another one, passing through a valley of intermediate deleterious states, was first raised by HALDANE (1 931) and WRIGHT (1 932). KIMURA (1 985) has formulated this problem at the molecular level. Consider a model with two loci (nucleotide sites). Mutations at these sites are assumed to be individually deleterious .but harmless (neutral) in appropriate combinations. This model of compensatory fitness interactions predicts that double mutants can easily become fixed in a population under continued mutation pressure and random genetic drift, when the two sites are closely linked. However, the rate ofjoint fixation may drop dramatically, as distance between sites increases and recombination breaks up favorable combinations. Compensatory fitness interactions may therefore play an important role in determining the size of a coevolvable genetic unit (“gene”). RNA secondary structure provides a unique opportunity to test this model. Mutations occurring in a pairing region of a secondary structural element are individually deleterious if they destabilize a functionally important structure. But fitness can be restored, when a compensatory mutation occurs that reestablishes the pairing potential. To examine the model of compensatory neutral mutations, we constructed a secondary structure of a large RNA, A d h pre-mRNA