A fundamental question in biology is how natural selection shapes the genetic variation responsible for metabolic variation among individuals. Several decades ago it became apparent that many metabolic enzymes are segregating for molecular variation in many organisms including humans. The long range goals of the study proposed will examine the extent to which metabolic variation is associated with molecular variation in the enzymes of universal central metabolic pathways. It will study these mechanisms in the fruit fly Drosophila melanogaster, a model organism for whom the entire genome was sequenced this year. Genetic disorders in metabolism are a major health concern from diabetes to obesity. Many of these disorders have their causes in the genes under investigation. The specific scientific objectives are several. (1) To determine which enzymes, genes and pathways are responding to natural selection. This will involve sequencing a set of genes involved in lipogenesis, glycolysis, gluconeogenesis, the NADH/NAD shuttles, and glutamate metabolism. From patterns of DNA and inferred protein sequence variation and geographic patterns associated with latitude, it will be determined which pathways steps are responding to natural selection to modulate metabolic pools and adapt to ethanol rich niches. (2) To study the functional differences associated with pathway steps seem to be carrying genetic variation associated with patterns of geographic variation. (3) Experimental manipulations will be carried out to evaluate the extent to which individual steps or enzymes can modulate metabolic pools and pathway fluxes. (4) The proximal selective causes associated with latitudinal variation will be investigated. These likely involve selection on delayed senescence in northern regions, as well as associated reallocation of metabolic pools away from reproduction. This will focus on the dichotomous variation of female reproduction diapause and its related phenotypes such as starvation resistance. Studies will begin to identify the genes responsible for the variation in this suite of traits that have cascading effects into the metabolic pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM045247-10
Application #
6721308
Study Section
Special Emphasis Panel (ZRG1-SSS-Y (03))
Program Officer
Eckstrand, Irene A
Project Start
1991-08-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
10
Fiscal Year
2004
Total Cost
$270,900
Indirect Cost
Name
State University New York Stony Brook
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Eanes, Walter F (2011) Molecular population genetics and selection in the glycolytic pathway. J Exp Biol 214:165-71
Merritt, Thomas J S; Kuczynski, Caitlin; Sezgin, Efe et al. (2009) Quantifying interactions within the NADP(H) enzyme network in Drosophila melanogaster. Genetics 182:565-74
Eanes, Walter F; Merritt, Thomas J S; Flowers, Jonathan M et al. (2009) Direct evidence that genetic variation in glycerol-3-phosphate and malate dehydrogenase genes (Gpdh and Mdh1) affects adult ethanol tolerance in Drosophila melanogaster. Genetics 181:607-14
Marks, Jessica A; Biermann, Christiane H; Eanes, Walter F et al. (2008) Sperm polymorphism within the sea urchin Strongylocentrotus droebachiensis: divergence between Pacific and Atlantic oceans. Biol Bull 215:115-25
Flowers, J M; Sezgin, E; Kumagai, S et al. (2007) Adaptive evolution of metabolic pathways in Drosophila. Mol Biol Evol 24:1347-54
Merritt, Thomas J S; Sezgin, Efe; Zhu, Chen-Tseh et al. (2006) Triglyceride pools, flight and activity variation at the Gpdh locus in Drosophila melanogaster. Genetics 172:293-304
Eanes, Walter F; Merritt, Thomas J S; Flowers, Jonathan M et al. (2006) Flux control and excess capacity in the enzymes of glycolysis and their relationship to flight metabolism in Drosophila melanogaster. Proc Natl Acad Sci U S A 103:19413-8
Matzkin, Luciano M; Merritt, Thomas J S; Zhu, Chen-Tseh et al. (2005) The structure and population genetics of the breakpoints associated with the cosmopolitan chromosomal inversion In(3R)Payne in Drosophila melanogaster. Genetics 170:1143-52
Merritt, Thomas J S; Duvernell, David; Eanes, Walter F (2005) Natural and synthetic alleles provide complementary insights into the nature of selection acting on the Men polymorphism of Drosophila melanogaster. Genetics 171:1707-18
Schmidt, Paul S; Matzkin, Luciano; Ippolito, Michael et al. (2005) Geographic variation in diapause incidence, life-history traits, and climatic adaptation in Drosophila melanogaster. Evolution 59:1721-32

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