Natural Genetic Variation and Epistasis in Aging

University Of Georgia (Uga), Athens GA

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Abstract

Recent efforts have seen great progress in the search for mutant genes that extend life spans in worms, flies and yeast. These discoveries have relied on strains that have been in the lab for hundreds of generations. Theoretical and empirical work now shows that under laboratory conditions, lab-adapted animals are often much shorter lived than their wild counterparts. At least in flies, genes that extend life span in lab strains may simply be ameliorating the effects of deleterious genes that have accumulated in the lab over many years. To date, no studies have examined the effect of life extending mutant genes in recently-derived genetic backgrounds. Here we propose to test the hypothesis that mutants that extend longevity in lab strains have little or no effect in recently derived, wild-caught strains in the fruit fly, D. melanogaster. More specifically, we predict that these longevity mutants will be effective in some but not all natural strains. To test this hypothesis, we will examine the effect of three longevity assurance genes (or 'LAGs')-methuselah, hSOD1 and Indy-in the genetic background of ten wild-caught isofemale lines. For each isofemale background, we will measure the effect of mutants on age-specific mortality, resistance to oxidative stress (paraquat) and resistance to heat shock. With these data, we will be able to determine 1) if LAGs extend longevity in a strain-specific manner or universally; and 2) if genetic variation for longevity is caused by epistatic interactions. If we find that the effect of one or more LAGs is strain specific, this could pave the way toward the eventual discovery of epistatically interacting networks of genes that affect longevity. By looking for interactions between LAGs and natural backgrounds, this research will provide a unique opportunity to determine the importance of epistasis to aging. Results from this work could lead to new and more effective approaches to identify genes that extend longevity. Finally, results from these pilot experiments will serve as the basis for a longer- term research proposal on the role that epistasis plays in the genetics of senescence.