Mutations in many genes interacting with each other and with the environment cause most common human diseases. However, these mutations are difficult to identify because the majority cause small phenotypic effects and genetic modifiers can alter the severity of a disease. Numerous genes of large effect are known, but the genes of modest effect that predispose certain individuals to disease are less well known and vary in populations. Therefore, the same mutation that causes a severe disease in one genetic background may not cause the same severity of disease in a different genetic background. Using the genetic background differences among individuals in a population, quantitative genetic studies can identify the genes that modify disease predisposition. Caenorhabditis elegans facilitates the identification of human disease genes because most cell-signaling pathways are conserved, especially the TGF-beta and insulin pathways. In this study, I will use C. elegans quantitative genetics coupled with classical genetic epistasis to identify the genes of both major and modest effects on conserved TGF-beta and insulin pathways. First, I will score a collection of recombinant inbred lines (RILs) created from the reference strain from England and a polymorphic strain from Hawaii for pathway phenotypes. These quantitative trait analyses will rapidly identify the major effect genes that control any phenotypic differences. Next, I will determine whether subtle genetic modifiers exist in other strain backgrounds by crossing extant mutations from the reference genetic background into the Hawaiian genetic background and scoring for suppression or enhancement of TGF-beta and insulin pathway phenotypes. Last, I will create sensitized RIL collections to facilitate the identification of modest-effect genes that alter TGF-beta and insulin pathway activities. Public Health Relevance: Common disease-causing mutations are time-consuming and costly to identify in humans. Because the TGF-beta and insulin pathways are similar in the simple nematode C. elegans as in humans, genes that modify these pathways can be rapidly and cheaply identified. These modifier genes will broaden our understanding of diseases associated with these pathways, like epithelia-derived cancers and diabetes, and suggest new therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM089007-02
Application #
7926998
Study Section
Special Emphasis Panel (ZRG1-F08-G (20))
Program Officer
Bender, Michael T
Project Start
2009-09-01
Project End
2011-05-31
Budget Start
2010-09-01
Budget End
2011-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$39,875
Indirect Cost
Name
Princeton University
Department
Type
Organized Research Units
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Andersen, Erik C; Shimko, Tyler C; Crissman, Jonathan R et al. (2015) A Powerful New Quantitative Genetics Platform, Combining Caenorhabditis elegans High-Throughput Fitness Assays with a Large Collection of Recombinant Strains. G3 (Bethesda) 5:911-20
Balla, Keir M; Andersen, Erik C; Kruglyak, Leonid et al. (2015) A wild C. elegans strain has enhanced epithelial immunity to a natural microsporidian parasite. PLoS Pathog 11:e1004583
Etienne, Veronique; Andersen, Erik C; Ponciano, José Miguel et al. (2015) The red death meets the abdominal bristle: polygenic mutation for susceptibility to a bacterial pathogen in Caenorhabditis elegans. Evolution 69:508-19
Andersen, Erik C; Bloom, Joshua S; Gerke, Justin P et al. (2014) A variant in the neuropeptide receptor npr-1 is a major determinant of Caenorhabditis elegans growth and physiology. PLoS Genet 10:e1004156
Felix, Marie-Anne; Jovelin, Richard; Ferrari, Celine et al. (2013) Species richness, distribution and genetic diversity of Caenorhabditis nematodes in a remote tropical rainforest. BMC Evol Biol 13:10
Andersen, Erik C (2011) PCR-directed in vivo plasmid construction using homologous recombination in baker's yeast. Methods Mol Biol 772:409-21