Deletion of a conserved regulatory element in the Drosophila Adh gene leads to increased alcohol dehydrogenase activity but also delays development

In vivo levels of enzymatic activity may be increased through either struct ural or regulatory changes. Here we use Drosophila melanogaster alcohol deh ydrogenase (ADH) in an experimental test for selective differences between these two mechanisms. The well-known ADH-Slow (S)/Fast (F) amino acid repla cement leads to a twofold increase in activity by increasing the catalytic efficiency of the enzyme. Disruption of a highly conserved, negative regula tory element in the Adh 3' UTR also leads to a twofold increase in activity , although this is achieved by increasing in vivo Adh mRNA and protein conc entrations. These two changes appear to be under different types of selecti on, with positive selection favoring the amino acid replacement and purifyi ng selection maintaining the 3' UTR sequence. Using transgenic experiments we show that deletion of the conserved 3' UTR element increases adult and l arval Adh expression in both the ADH-F and ADH-S genetic backgrounds. Howev er, the 3' UTR deletion also leads to a significant increase in development al time in both backgrounds. ADH allozyme type has no detectable effect on development. These results demonstrate a negative fitness effect associated with Adh overexpression. This provides a mechanism whereby natural selecti on can discriminate between alternative pathways of increasing enzymatic ac tivity.