Molecular genetics has identified candidate genes with affects on longevity. Our awareness of these loci derives from analyses of rare, highly penetrant mutants, and from transgenic manipulation. However, for the general population it is presently unknown whether and to what extent there exist at these loci less penetrant but more common alleles. This question is crucial for understanding the broad impact of such genes on population health and aging. The project proposed here intends to determine whether natural polymorphisms of candidate longevity-affecting loci are associated with variation in senescence phenotypes. The study uses Drosophila as a model system since powerful molecular and genetic techniques can be applied to candidate genes which have homologous sequences and functions among vertebrates. Nucleotide polymorphisms within the genes hsp70 and Cu/ZnSOD will be discovered from a sample of 100 third chromosomes extracted from a wild population. Senescence related phenotypes with known attribution to these loci will be measured for each extraction strain, specifically demographic aging, heat induced longevity extension, resistance to heat and oxidative stress, and gene expression. Statistical associations among phenotypes and polymorphism will be sought with regression analysis under a permuted threshold design. Natural alleles will be scored for phenotypes in homozygous and heterozygous state in isogenic longevity-selected and control strains. The genotype-phenotype associations detected with this design will be of broad significance to the problem of genetic variation for longevity in general populations.
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