Quantitative Molecular Genetics of Longevity in Drosophila melanogaster.

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Title: Quantitative Molecular Genetics of Longevity in Drosophila melanogaster.
Author: Thornsberry, Gretchen Lindsay Geiger
Advisors: Bruce Weir, Committee Member
Trudy F. C. Mackay, Committee Chair
Greg Gibson, Committee Member
Michael Purugganan, Committee Member
Abstract: Limited life span and senescence are universal phenomena, controlled by genetic and environmental factors whose interactions both limit life span and generate variation in life span between individuals, populations and species. To understand the genetic architecture of aging it is necessary to know what loci affect variation in life span, what are the allelic effects at these loci and what molecular polymorphisms define quantitative trait locus (QTL) alleles. Here, quantitative complementation tests were used to determine whether candidate life span genes such as Superoxide dismutase (Sod), Catalase (Cat), heat shock proteins, DNA repair enzymes, glucose metabolism or male accessory gland proteins interact genetically with naturally occurring QTL affecting variation in life span in Drosophila melanogaster. Inbred strains derived from a natural population were crossed to stocks containing null mutations or deficiencies uncovering the above genes. Life span of the heterozygous progeny was assayed. A significant cross (mutant versus wild-type allele of the candidate gene) by inbred line interaction term from analysis of variance of the life span data indicates a genetic interaction between the candidate gene allele and the naturally occurring life span QTL. Of the sixteen candidate regions and genes tested, Df(2L)cl7, Df(3L)Ly, Df(3L)AC1, Df(3R)e-BS2, and &#945;-Glycerol phosphate dehydrogenase showed significant failure to complement wild-type alleles in both sexes, and an Alcohol dehydrogenase mutant failed to complement in females. Several genes known to regulate life span (Sod, Cat, and rosy) complemented the life span effects of alleles, suggesting little natural variation affecting longevity at these loci, at least in this sample of alleles. Quantitative complementation tests are therefore useful for identifying candidate genes contributing to segregating genetic variation in life span in nature. Mutations in most vital genes can potentially affect life history traits, but it is not known what subset of these loci harbor naturally occurring variation affecting the rate of aging and the ability to resist stress. While the gene Punch (Pu) was not significant in the quantitative complementation test, it has been implicated in starvation resistance. As there is a direct relationship between stress resistance and longevity, Pu, which encodes GTP cyclohydrolase (GTPCH), is a candidate gene for associating molecular variation and variation in life pan. GTPCH regulates the catecholamine biosynthesis pathway by catalyzing the formation of tetrahydrobiopterin, the rate-limiting molecule, and by regulating tyrosine hydroxylase, a key enzyme in the pathway. The extent to which molecular variation at Pu contributes to phenotypic variation was assessed by associating single nucleotide polymorphisms (SNPs) at Pu with longevity. Nucleotide variation was determined for ten Pu alleles. Genotypes of 28 SNPs were determined on a sample of 178 isogenic second chromosomes sampled from the Raleigh, USA population and substituted into the highly inbred Samarkand background. Life span was determined for the chromosome substitution lines and the association between longevity phenotype and SNP genotype was assessed for each polymorphic marker. Three SNPs were significantly associated with life span (C6291A, P = 0.0183; A6389T, P = 0.0466; G6894C, P = 0.0024). None of these SNPs was significant individually following a permutation test accounting for multiple tests and partially correlated markers. However, the three SNPs associated with life span were in global linkage disequilibrium. Haplotypes of these SNPs were highly significantly associated with variation in longevity (P < 0.0001), and accounted for 13.5 % of the genetic variance and 1.86 % of the phenotypic variance in longevity attributable to chromosomes 2. As Pu is a regulator of the catecholamine biosynthetic pathway, these findings suggest the importance of the production of biogenic amines in determining variation for longevity.
Date: 2004-08-18
Degree: PhD
Discipline: Genetics
URI: http://www.lib.ncsu.edu/resolver/1840.16/3221

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