Genetics of Cocaine Sensitivity in Drosophila

果蝇可卡因敏感性的遗传学

• 批准号: 10370859
• 负责人: Robert R. H Anholt
• 金额: $ 49.54万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370859
• 关键词: Affect; Alcohols; Alleles; Animal Model; Atlases; Behavior; Biological Assay; Biological Process; Brain; CRISPR/Cas technology; Candidate Disease Gene; Cells; Cocaine; Consumption; Crime; Data; Drosophila genus; Drosophila melanogaster; Drug Addiction; Drug Costs; Drug Exposure; Drug abuse; Elements; Etiology; Exposure to; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Models; Genetic Transcription; Genetic Variation; Genome; Genomic Segment; Health; Healthcare; Human; Imprisonment; Inbreeding; Individual; Maps; Molecular; National Institute of Drug Abuse; Nicotine; Orthologous Gene; Persons; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Public Health; Quantitative Trait Loci; Resolution; Sample Size; Societies; Substance abuse problem; System; Tobacco use; Untranslated RNA; Variant; causal variant; cocaine exposure; cocaine use; comorbidity; cost; fly; gene regulatory network; genetic analysis; genetic association; genetic resource; genetic risk factor; genetic variant; genome wide association study; illicit drug use; in vivo; insight; network architecture; neuropsychiatric disorder; population based; preference; productivity loss; psychostimulant; rare variant; socioeconomics; stimulant use; trait; transcriptome sequencing; translational potential; translational study

SUMMARY Illegal use of cocaine and other drugs is a worldwide health problem. The National Institute on Drug Abuse estimates the total costs of drug abuse and addiction due to use of tobacco, alcohol and illegal drugs at $820 billion a year, making substance abuse the most costly public health problem in the nation. Illicit drug use alone accounts for $193 billion in health care, productivity loss, crime, incarceration, and drug enforcement. In humans, susceptibility to the effects of cocaine and other drugs has a strong genetic component, but little progress has been made in identifying the underlying variants and genes, in part due to difficulty in obtaining sufficiently large sample sizes because of criminalization of substance abuse; variation in drug exposure, including simultaneous exposure to multiple drugs, alcohol and nicotine; and comorbidity with other neuropsychiatric disorders. These problems can be mitigated using model organisms, such as Drosophila melanogaster. In addition to benefits of low rearing costs, small size and a short generation interval, Drosophila has a wealth of publically available genetic resources. Importantly, many effects of psychostimulants on people are replicated in flies. Approximately 67% of fly genes have human orthologs, and therefore insights gained from Drosophila have translational potential. During the past period of support, we have used the D. melanogaster Genetic Reference Panel of inbred wild-derived fly strains with fully sequenced genomes, and outbred advanced intercross populations (AIPs) derived from DGRP lines, to perform genome wide association (GWA) analyses of drug consumption behaviors and gene expression. These analyses showed that variants associated with drug consumption phenotypes were largely located in non-coding genomic regions, and presumably exert their phenotypic effects via modulation of gene regulation. We derived gene regulatory networks from naturally occurring genetic variation in gene expression and constructed an atlas of gene expression changes in the Drosophila brain following cocaine exposure at single cell resolution. The challenge now is to understand how variants act jointly to affect variation in drug preference, and to determine the underlying molecular networks using systems genetics analyses. Here, we propose to use 1200 new DGRP lines to map naturally occurring variants and genes associated with cocaine preference with greatly increased power and precision than our previous studies, perform a systems genetic analysis to infer causal regulatory networks associated with cocaine preference, and use germline gene editing to prove causality of the genetic associations with cocaine preference and gene regulatory networks. Information obtained from these studies can serve as a blueprint for subsequent translational studies in mammalian systems and human populations based on orthology and evolutionary conservation of fundamental biological processes, and expand the genetic framework associated with variation in human drug susceptibility beyond the narrow range of candidate genes examined to date.

概括 非法使用可卡因和其他药物是全球健康问题。美国国家药物滥用研究所 估计由于使用烟草，酒精和非法药物而导致的药物滥用和成瘾的总成本为820美元 每年十亿美元，使滥用药物成为美国最昂贵的公共卫生问题。单独使用非法毒品 账户为1930亿美元的医疗保健，生产力损失，犯罪，监禁和毒品执法。在 人类，对可卡因和其他药物影响的敏感性具有很强的遗传成分，但很少 在识别基本变体和基因方面取得了进展，部分原因是难以获得 由于将药物滥用定为定罪，样本量足够大；药物暴露的变化， 包括同时接触多种药物，酒精和尼古丁；和其他与其他合并症 神经精神疾病。可以使用果蝇等模型生物来减轻这些问题 Melanogaster。除了较低的饲养成本，小尺寸和短期间隔外，果蝇还 拥有大量公开可用的遗传资源。重要的是，心理刺激剂对人的许多影响 被苍蝇复制。大约67％的飞基因具有人类直系同源物，因此获得了见解 来自果蝇具有翻译潜力。在过去的支持期间，我们使用了D。 Melanogaster遗传参考面板，具有完全测序基因组的近交野生蝇菌株和 源自DGRP系的近亲晚期间交叉种群（AIPS），以执行基因组范围的关联 （GWA）对药物消耗行为和基因表达的分析。这些分析表明变体 与药物消耗表型相关 大概通过调节基因调节发挥其表型作用。我们得出基因调节 来自基因表达中天然遗传变异的网络，并构建了基因的地图集 在单细胞分辨率下可卡因暴露后，果蝇脑的表达变化。挑战 现在是了解变体如何共同作用以影响药物偏好的变异，并确定 使用系统遗传学分析的基础分子网络。在这里，我们建议使用1200个新DGRP 绘制自然发生的变体和与可卡因偏好相关的基因，并大大增加 与以前的研究相比，功率和精度，进行系统遗传分析以推断因果调节 与可卡因偏好相关的网络，并使用种系基因编辑来证明遗传因果关系 与可卡因偏好和基因调节网络的关联。从这些研究获得的信息 可以用作哺乳动物系统和人类种群的随后翻译研究的蓝图 基于对基本生物学过程的矫正和进化保护，并扩展 与人类药物易感性变化相关的遗传框架以外的候选范围 迄今为止检查的基因。