MAINTENANCE OF PRE-MESSENGER-RNA SECONDARY STRUCTURE BY EPISTATIC SELECTION

Linkage disequilibrium between polymorphisms in a natural population m ay result from various evolutionary forces, including random genetic d rift due to sampling of gametes during reproduction, restricted migrat ion between subpopulations in a subdivided population, or epistatic se lection, In this report, we present evidence that the majority of sign ificant linkage disequilibria observed in introns of the alcohol dehyd rogenase locus (Adh) of Drosophila pseudoobscura are due to epistatic selection maintaining secondary structure of precursor mRNA (pre-mRNA) . Based on phylogenetic-comparative analysis and a likelihood approach , we propose secondary structure models of Adh pre mRNA for the region s of the adult intron and intron 2 where clustering of linkage disequi libria has been observed, Furthermore, we applied the likelihood ratio test to the phylogenetically predicted secondary structure in intron 1. In contrast to the other two structures, polymorphisms associated w ith the more conserved stem-loop structure of intron 1 are in low freq uency, and linkage disequilibria have not been observed, These finding s are qualitatively consistent with a model of compensatory fitness in teractions, This model assumes that mutations disrupting pairing in a secondary structural element are individually deleterious if they dest abilize a functionally important structure; a second ''compensatory'' mutation, however, may restabilize the structure and restore fitness.