Identifying the genetic basis of variation in complex traits is a grand challenge. Genome-wide association studies suggest that many alleles with small effects may be responsible for many common diseases. When allelic effects are individually small, identification of these alleles is a daunting task. A mutation may not cause disease in a single molecular step, but instead interact with other mutations or cascade through intermediate molecular pathways eventually resulting in disease traits. Identifying the networks which underlie variation in disease traits and understanding how perturbations in these networks affect phenotypes may be a more efficient approach to identifying therapeutic targets. We propose to test this approach by building predictive genotype to phenotype models for complex behaviors in D. melanogaster and D.simulans (courtship and locomotion) assayed under standard conditions and during ethanol exposure (a model for environmental perturbations or disease states). By moving beyond descriptive studies in single populations to causative directional models which are predictive in novel conditions, shared and specific network structures will be identified. Networks which do not differ between sexes, species or environmental conditions are good candidates for comparison to other model systems or to humans. Highly conserved regulatory relationships are most likely critical for viability or fertility. Divergence in the regulation of individual genes or changes in network structure highlight the possible evolution of regulatory interactions among genes and identify candidate polymorphisms, genes and networks which may contribute to the evolution of novel traits, such as increased ethanol tolerance. Alcohol dependency affects approximately 18 million people in the USA, impacting health and quality of life. Ethanol has severe effects on human behavior, resulting in euphoria and sedation. In addition, intoxication can increase aggression, cause impotence, and decrease sexual inhibition and locomotor skills. The effects of alcohol and risk for alcoholism have a strong and complex genetic component, but are also mediated by the environment. While there are some large effect loci (e.g. ADH, ALDH and GABA receptor genes), much of the heritability remains unexplained. Drosophila have similar responses to ethanol, with courtship and locomotion affected by exposure. We will bring the power of Drosophila genetics to bear on this problem with an in depth examination of two species and their response to ethanol. We will directly test the hypothesis that conserved networks correspond to a higher degree of translatability of prediction of phenotypic outcomes across species. In addition, we will determine how robust these predictions are to gene by environment effects by exposing both populations to ethanol.

Public Health Relevance

Alcohol dependency affects approximately 18 million people in the USA, impacting health and quality of life. The effects of alcohol and risk for alcoholism have a genetic component mediated by the environment and include increased aggression, impotence, and decreased sexual inhibition and decreased locomotor skills. We will bring the power of Drosophila genetics to bear on this problem with an examination of two species and their response to ethanol.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM102227-03
Application #
8678952
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Janes, Daniel E
Project Start
2012-09-17
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Florida
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Signor, Sarah A; New, Felicia N; Nuzhdin, Sergey (2018) A Large Panel of Drosophila simulans Reveals an Abundance of Common Variants. Genome Biol Evol 10:189-206
Signor, Sarah; Nuzhdin, Sergey (2018) Dynamic changes in gene expression and alternative splicing mediate the response to acute alcohol exposure in Drosophila melanogaster. Heredity (Edinb) 121:342-360
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Signor, Sarah A; Abbasi, Mohammad; Marjoram, Paul et al. (2017) Social effects for locomotion vary between environments in Drosophila melanogaster females. Evolution 71:1765-1775
Newman, Jeremy R B; Conesa, Ana; Mika, Matthew et al. (2017) Disease-specific biases in alternative splicing and tissue-specific dysregulation revealed by multitissue profiling of lymphocyte gene expression in type 1 diabetes. Genome Res 27:1807-1815
Signor, Sarah A; Arbeitman, Michelle N; Nuzhdin, Sergey V (2016) Gene networks and developmental context: the importance of understanding complex gene expression patterns in evolution. Evol Dev 18:201-9
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Fear, Justin M; León-Novelo, Luis G; Morse, Alison M et al. (2016) Buffering of Genetic Regulatory Networks in Drosophila melanogaster. Genetics 203:1177-90
Kao, Joyce Y; Zubair, Asif; Salomon, Matthew P et al. (2015) Population genomic analysis uncovers African and European admixture in Drosophila melanogaster populations from the south-eastern United States and Caribbean Islands. Mol Ecol 24:1499-509

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