Genetics of Alcohol Sensitivity in Drosophila

果蝇酒精敏感性的遗传学

• 批准号: 7743583
• 负责人: TRUDY F. MACKAY
• 金额: $ 32.52万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743583
• 关键词: Address; Affect; Alcohol abuse; Alcohol dependence; Alcoholism; Alcohols; Alleles; Analysis of Variance; Animal Model; Architecture; Award; Behavior; Behavioral; Biological Models; Candidate Disease Gene; Cardiovascular Diseases; Cessation of life; Chronic; Complex; DNA; Data; Development; Drosophila genus; Drosophila melanogaster; Economics; Environmental Risk Factor; Exploratory/Developmental Grant; Future; Genes; Genetic; Genetic Complementation Test; Genetic Models; Genetic Polymorphism; Genome; Genome Scan; Genotype; Goals; Human; Individual; Induced Mutation; Injury; Insertion Mutation; Maps; Medical; Modeling; Molecular; Mutation; Nature; Neurologic; Nucleotides; Parenting behavior; Pattern; Phenotype; Phosphorus; Population; Population Genetics; Population Heterogeneity; Predisposing Factor; Quantitative Trait Loci; Research; Resistance; Resolution; Staging; Stress; Systems Biology; Testing; Tissues; Traffic accidents; Transcript; Transcriptional Regulation; Transgenic Organisms; United States; Variant; alcohol behavior; alcohol effect; alcohol sensitivity; base; comparative genomics; design; fly; gastrointestinal; insight; molecular marker; novel; programs; response; social; socioeconomics; trait

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.

酗酒是世界范围内许多医疗、社会和经济问题的根源。而酒精是其一