Alcoholism is the cause of many medical, social and economic problems worldwide. Whereas alcohol is one of the most widely abused substances, individuals vary greatly in alcohol sensitivity and propensity for developing alcohol dependence. However, our understanding of the genetic mechanisms and the environmental triggers responsible for this variation in alcohol-related behavior is far from complete. The difficulty arises because alcohol-related behaviors are complex traits, and individual variation is attributable to multiple interacting genes with small effects, the expression of which depends on environmental factors. The long-term goal of this project is to elucidate the genetic architecture of alcohol sensitivity and tolerance in a powerful genetic model system, Drosophila melanogaster, and to usethis information to gain insights into the genetic factors that predispose to the development of alcohol dependence in people.
The Specific Aims of this proposal are: (1) to characterize prevously identified P-element insertional mutations affecting sensitivity and resistance to the intoxicating effects of ethanol in greater molecular and phenotypic detail, and to determine to what extent these genes interact; (2) to use a systems biology approach, in which whole genome transcriptional profiling is applied to P-element insert lines affecting alcohol sensitivity and resistant and sensitive artificial selection lines, to identify co-regulated genetic networks affecting alcohol sensitivity; (3) to perform a high resolution genome scan for quantitative trait loci affecting naturally occurring variation in alcohol sensitivity between lines selected for increased and decreased alcohol sensitivity, and identify positional candidate genes that contribute to differences in alcohol sensitivity in the selection lines; and (4) to assess the extent to which polymorphisms in candidate genes affecting alcohol sensitivity discovered in the previous specific aims are associated with naturally occurring variation in alcohol sensitivity. Approximately 14 million people in the United States suffer from alcoholism. Chronic alcohol abuse is responsible for a vast number of traffic accidents that result in serious injury or death; neurological, gastrointestinal and cardiovascular disorders; and socio-economic problems, including increasedaggressive behavior with adverse impacts on parenting and marital stability. Determining what genetic factors affect alcohol-related behavior is challenging in humans, but can be addressed more readily in model organisms. Achieving a comprehensive description of the genetic basis of alcohol sensitivity in Drosophila will facilitate a future comparative genomic approach in which we directly incorporate this information in human linkage and association studies to identify genes that confer liability for development of alcohol dependence in human populations.
| Rohde, Palle Duun; Østergaard, Solveig; Kristensen, Torsten Nygaard et al. (2018) Functional Validation of Candidate Genes Detected by Genomic Feature Models. G3 (Bethesda) 8:1659-1668 |
| Mackay, Trudy F C; Huang, Wen (2018) Charting the genotype-phenotype map: lessons from the Drosophila melanogaster Genetic Reference Panel. Wiley Interdiscip Rev Dev Biol 7: |
| Morozova, Tatiana V; Hussain, Yasmeen; McCoy, Lenovia J et al. (2018) A Cyclin E Centered Genetic Network Contributes to Alcohol-Induced Variation in Drosophila Development. G3 (Bethesda) 8:2643-2653 |
| Morgante, Fabio; Huang, Wen; Maltecca, Christian et al. (2018) Effect of genetic architecture on the prediction accuracy of quantitative traits in samples of unrelated individuals. Heredity (Edinb) 120:500-514 |
| Anholt, Robert R H; Mackay, Trudy F C (2018) The road less traveled: from genotype to phenotype in flies and humans. Mamm Genome 29:5-23 |
| Fochler, S; Morozova, T V; Davis, M R et al. (2017) Genetics of alcohol consumption in Drosophila melanogaster. Genes Brain Behav 16:675-685 |
| Rohde, Palle Duun; Gaertner, Bryn; Ward, Kirsty et al. (2017) Genomic Analysis of Genotype-by-Social Environment Interaction for Drosophila melanogaster Aggressive Behavior. Genetics 206:1969-1984 |
| Garlapow, Megan E; Everett, Logan J; Zhou, Shanshan et al. (2017) Genetic and Genomic Response to Selection for Food Consumption in Drosophila melanogaster. Behav Genet 47:227-243 |
| Garcia, Júlia Frankenberg; Carbone, Mary Anna; Mackay, Trudy F C et al. (2017) Regulation of Drosophila Lifespan by bellwether Promoter Alleles. Sci Rep 7:4109 |
| Bushnell, Philip J; Ward, William O; Morozova, Tatiana V et al. (2017) Editor's Highlight: Genetic Targets of Acute Toluene Inhalation in Drosophila melanogaster. Toxicol Sci 156:230-239 |
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