Protein variation in ADH and ADH-RELATED in Drosophila pseudoobscura: Linkage disequilibrium between single nucleotide polymorphisms and protein alleles

A 3.5-kb segment of the alcohol dehydrogenase (Adh) region that includes th e Adh and Adh-related genes vas sequenced in 139 Drosophila pseudoobscura s trains collected from 13 populations. The Adh gene encodes four protein all eles and rejects a neutral model of protein evolution with the McDonald-Kre itman test, although the number of segregating synonymous sites is too high to conclude that adaptive selection has operated. The Adh-related gene enc odes 18 protein haplotypes and fails to reject art equilibrium neutral mode l. The populations fail to show significant geographic differentiation of t he Adh-related haplotypes. Eight of 404 single nucleotide polymorphisms (SN Ps) in the Adh region were in significant linkage disequilibrium with three ADHR protein alleles. Coalescent simulations vith and without recombinatio n were used to derive the expected levels of significant linkage disequilib rium between SNPs and IS protein haplotypes. Maximum levels of linkage dise quilibrium are expected for protein alleles at moderate frequencies. In coa lescent models without recombination, linkage disequilibrium decays between SNPs and high frequency haplotypes because common alleles mutate to haplot ypes that are rare or that reach moderate frequency. The implication of thi s study is that linkage disequilibrium mapping has the highest probability of success with disease-causing alleles at frequencies of 10%.