Abstract
Mutational analyses in model organisms have shown that genes affecting metabolism and stress resistance regulate life span1, but the genes responsible for variation in longevity in natural populations are largely unidentified. Previously, we mapped quantitative trait loci (QTLs) affecting variation in longevity between two Drosophila melanogaster strains2. Here, we show that the longevity QTL in the 36E;38B cytogenetic interval on chromosome 2 contains multiple closely linked QTLs, including the Dopa decarboxylase (Ddc) locus. Complementation tests to mutations show that Ddc is a positional candidate gene for life span in these strains. Linkage disequilibrium (LD) mapping in a sample of 173 alleles from a single population shows that three common molecular polymorphisms in Ddc account for 15.5% of the genetic contribution to variance in life span from chromosome 2. The polymorphisms are in strong LD, and the effects of the haplotypes on longevity suggest that the polymorphisms are maintained by balancing selection. DDC catalyzes the final step in the synthesis of the neurotransmitters, dopamine and serotonin3. Thus, these data implicate variation in the synthesis of bioamines as a factor contributing to natural variation in individual life span.
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References
Finch, C.E. & Ruvkun, G. The genetics of aging. Annu. Rev. Genomics Hum. Genet. 2, 435–362 (2001).
Leips, J. & Mackay, T.F.C. The complex genetic architecture of Drosophila life span. Exp. Aging Res. 28, 361–390 (2002).
Livingstone, M.S. & Tempel, B.L. Genetic dissection of monoamine neurotransmitter synthesis in Drosophila. Nature 303, 67–70 (1983).
Finch, C.E. & Tanzi, R.E. Genetics of aging. Science 278, 407–411 (1997).
Pasyukova, E.G., Vieira, C. & Mackay, T.F.C. Deficiency mapping of quantitative trait loci affecting longevity in Drosophila melanogaster. Genetics 156, 1129–1146 (2000).
Stathakis, D.G. et al. The genetic and molecular organization of the Dopa decarboxylase gene cluster of Drosophila melanogaster. Genetics 141, 629–655 (1995).
Blenau, W. & Baumann, A. Molecular and pharmacological properties of insect bioamine receptors: lessons from Drosophila melanogaster and Apis mellifera. Arch. Insect Biochem. Phys. 48, 13–38 (2001).
Lunan, K.D. & Mitchell, H.K. The metabolism of tyrosine O phosphate in Drosophila. Arch. Biochem. Biophys. 132, 450–456 (1969).
Fry, J.D., Heinsohn, S.L. & Mackay, T.F.C. Heterosis for viability, fecundity, and male fertility in Drosophila melanogaster: comparison of mutational and standing variation. Genetics 148, 1171–1188 (1998).
Watterson, G.A. On the number of segregating sites in genetical models without recombination. Theor. Popul. Biol. 7, 256–276 (1975).
Nei, M. & Tajima, F. DNA polymorphism detectable by restriction endonucleases. Genetics 97, 145–163 (1981).
Fu, Y.-X. & Li, W.-H. Statistical tests of neutrality of mutations. Genetics 133, 693–709 (1993).
Lundell, M.J. & Hirsh, J. Regulation of the Dopa decarboxylase gene during Drosophila development. Adv. Dev. Biochem. 3, 55–86 (1994).
Tajima, F. Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123, 585–595 (1989).
Hudson, R.R., Kreitman, M. & Aguadé, M. A test of neutral molecular evolution based on nucleotide data. Genetics 116, 153–159 (1987).
McDonald, J.H. & Kreitman, M. Adaptive protein evolution at the Adh locus in Drosophila. Nature 351, 652–654 (1991).
Hudson, R.R. Estimating the recombination parameter of a finite population model without selection. Genet. Res. 50, 245–250 (1987).
Aquadro, C.F., Jennings, R.M., Bland, M.M., Laurie, C.C. & Langley, C.H. Patterns of naturally occurring restriction map variation, DDC activity variation and linkage disequilibrium in the dopa decarboxylase gene region of Drosophila melanogaster. Genetics 132, 443–452 (1992).
Sabeti, P.C. et al. Detecting recent positive selection in the human genome from haplotype structure. Nature 419, 832–837 (2002).
Williams, G.C. Pleiotropy, natural selection and the evolution of senescence. Evolution 11, 398–411 (1957).
Rose, M.R. & Charlesworth, B. A test of evolutionary theories of senescence. Nature 287, 141–142 (1980).
Stam, L.F. & Laurie, C.C. Molecular dissection of a major gene effect on a quantitative trait: the level of alcohol deydrogenase expression in Drosophila melanogaster. Genetics 144, 1559–1564 (1996).
Sze, J.Y., Victor, M., Loer, C., Shi, Y. & Ruvkun, G. Food and metabolic signalling defects in a Caenorhabditis elegans serotonin synthesis mutant. Nature 403, 560–564 (2000).
De Benedictis, G. et al. Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD2). Eur. J. Hum. Genet. 6, 534–541 (1998).
De Luca, M. et al. Sex-specific longevity associations defined by Tyrosine Hydroxylase-Insulin-Insulin Growth Factor 2 haplotypes on the 11p15.5 chromosomal region. Exp. Gerontol. 36, 1663–1671 (2001).
Pasyukova, E.G. & Nuzhdin, S.V. Doc and copia instability in an isogenic Drosophila melanogaster stock. Mol. Gen. Genet. 240, 302–306 (1993).
Lyman, R.F., Lawrence, F., Nuzhdin, S.V. & Mackay, T.F.C. Effects of single P element insertions on bristle number and viability in Drosophila melanogaster. Genetics 143, 277–292 (1996).
Ronaghi, M., Uhlén, M. & Nyrén, P. Sequencing method based on real-time pyrophosphate. Science 281, 363–365 (1998).
Lyman, R.F., Lai, C. & Mackay, T.F.C. Linkage disequilibrium mapping of molecular polymorphisms at the scabrous locus associated with naturally occurring variation in bristle number in Drosophila melanogaster. Genet. Res. 74, 303–311 (1999).
Rozas, J. & Rozas, R. DnaSP version 3: an integrated program for molecular population genetics and molecular evolution analysis. Bioinformatics 15, 174–175 (1999)
Acknowledgements
We thank R. Anholt, C. Langley, J. Leips and J. O'Donnell for comments on the manuscript. This work was supported by grants from the US National Institutes of Health, the Russian Fund of Basic Research and the Russian Academy of Science. This is a publication of the W. M. Keck Center for Behavioral Biology.
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De Luca, M., Roshina, N., Geiger-Thornsberry, G. et al. Dopa decarboxylase (Ddc) affects variation in Drosophila longevity. Nat Genet 34, 429–433 (2003). https://doi.org/10.1038/ng1218
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DOI: https://doi.org/10.1038/ng1218
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