Most biological traits including common diseases have a strong but poorly understood genetic basis. Recent work suggests that a complex mixture of common and rare variants shape most biological traits - their exact effects mediated by extensive genetic interactions and organismal age. These observations are mainly correlative as little is known about the mechanisms that generate epistasis and age-dependence. Improved understanding of these processes could identify principals useful for predicting how causal factors act in novel genetic backgrounds and therapeutic techniques to take advantage of their non-linear effects to ameliorate disease. The broad objective of the proposed research is the identification of causative genetic variants affecting reproduction in C. elegans with age- dependent effect sizes and epistatic interactions. Once in hand, we will mechanistically dissect their causes in the context of organ and multicellular circuit function. We will study how life history changes in sperm number, a limited resource necessary for reproduction, creates age-dependent genetic architecture. Finally we will study how epistasis and aging are shaped by the function of the underlying neural circuit responsible for regulation of reproduction. These experiments will leverage C. elegans tractability to identify principles relevant to the study of human diseases.

Public Health Relevance

Most common diseases have a strong but complex genetic component. Understanding their genetic underpinnings will allow for their predictions and suggest targets for their amelioration. We will identify how age and epistasis affect traits in model organisms with the goal of identifying principals that can be applied to better predict the genetic variants responsible for human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM114170-03
Application #
9321149
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Janes, Daniel E
Project Start
2015-08-01
Project End
2020-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Georgia Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30318
Ramakrishnan Varadarajan, Ajay; Mopuri, Rohini; Streelman, J Todd et al. (2018) Genome-wide protein phylogenies for four African cichlid species. BMC Evol Biol 18:1
Zhao, Yuehui; Long, Lijiang; Xu, Wen et al. (2018) Changes to social feeding behaviors are not sufficient for fitness gains of the Caenorhabditis elegans N2 reference strain. Elife 7:
Campbell, Richard F; McGrath, Patrick T; Paaby, Annalise B (2018) Analysis of Epistasis in Natural Traits Using Model Organisms. Trends Genet 34:883-898
Baran, Nicole M; McGrath, Patrick T; Streelman, J Todd (2017) Applying gene regulatory network logic to the evolution of social behavior. Proc Natl Acad Sci U S A 114:5886-5893
McGrath, Patrick T (2017) Neurobiology: A genetic cause of age-related decline. Nature 551:179-180
Zhuo, Weipeng; Lu, Hang; McGrath, Patrick T (2017) Microfluidic platform with spatiotemporally controlled micro-environment for studying long-term C. elegans developmental arrests. Lab Chip 17:1826-1833
Evans, Kathryn S; Zhao, Yuehui; Brady, Shannon C et al. (2017) Correlations of Genotype with Climate Parameters Suggest Caenorhabditis elegans Niche Adaptations. G3 (Bethesda) 7:289-298
Large, Edward E; Padmanabhan, Raghavendra; Watkins, Kathie L et al. (2017) Modeling of a negative feedback mechanism explains antagonistic pleiotropy in reproduction in domesticated Caenorhabditis elegans strains. PLoS Genet 13:e1006769
Greene, Joshua S; Brown, Maximillian; Dobosiewicz, May et al. (2016) Balancing selection shapes density-dependent foraging behaviour. Nature 539:254-258
Large, Edward E; Xu, Wen; Zhao, Yuehui et al. (2016) Selection on a Subunit of the NURF Chromatin Remodeler Modifies Life History Traits in a Domesticated Strain of Caenorhabditis elegans. PLoS Genet 12:e1006219

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