Opposing fitness effects contribute to maintenance of polymorphism at a QTN in Aldehyde dehydrogenase. Mahul Chakraborty, James Fry. Department of Biology, University of Rochester, Rochester, NY.

   Resistance to ethanol is a crucial physiological adaptation in Drosophila melanogaster. Quantitative variation in this trait follows a worldwide clinal pattern, wherein flies from temperate populations are more resistant to ethanol than their tropical counterparts. Mitochondrial aldehyde dehydrogenase (DmALDH) contributes to this adaptation by detoxifying acetaldehyde, the breakdown product of ethanol. An Aldh replacement SNP changes a highly conserved leucine residue, located close to the predicted active site, to phenylalanine. The Phe allele is rare in the tropics but present in most temperate populations, suggesting it may be beneficial for ethanol metabolism. Nonetheless, the frequency of the Phe allele is usually no greater than 10-20%, raising the question of why it does not sweep to fixation. In silico analysis suggests that the substitution reduces the volume of the active site, resulting in improved fit for acetaldehyde, but poorer fit for larger aldehydes, which are continuously generated as byproducts of normal respiration. This prediction was confirmed by kinetic studies using purified recombinant enzyme: the Phe form, compared to the Leu form, has a higher turnover rate for acetaldehyde, but lower turnover rate for larger aldehydes. Consistent with the kinetic data, transgenic flies homozygous for the Phe allele are more resistant to ethanol than those homozygous for the Leu allele. In the absence of ethanol, however, Phe flies have markedly lower overall fitness than Leu flies. This difference is likely due in whole or part to lower ability of the Phe form to detoxify aldehydes generated by normal mitochondrial oxidative stress, as suggested by lower resistance of Phe flies to elevated oxidative stress than Leu flies. Thus, the advantage of Phe arising from faster ethanol detoxification is undermined by its deleterious effect on an important ancestral function, protection from mitochondrial oxidative stress. Our results give a rare example of an ecologically-relevant fitness trade-off caused by a single SNP.