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一个世界性的健康问题。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 每年数十亿美元，使药物滥用成为美国代价最高的公共卫生问题。单独使用违禁药物 医疗保健、生产力损失、犯罪、监禁和禁毒执法造成了 1,930 亿美元的损失。在 人类对可卡因和其他药物作用的易感性具有很强的遗传成分，但很少 在识别潜在的变异和基因方面已经取得了进展，部分原因是难以获得 由于将药物滥用定为刑事犯罪，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；以及与其他疾病的合并症 神经精神疾病。这些问题可以通过模型生物来缓解，例如果蝇 黑腹果蝇。果蝇除了饲养成本低、体型小、世代间隔短等优点外， 拥有丰富的公共遗传资源。重要的是，精神兴奋剂对人有许多影响 在果蝇中复制。大约 67% 的果蝇基因具有人类直向同源物，因此获得了见解 来自果蝇的具有转化潜力。在过去的支持期间，我们使用了 D. 具有完全测序基因组的近交野生果蝇品系的黑腹果蝇遗传参考面板，以及 远交源自 DGRP 品系的高级杂交群体 (AIP)，以进行全基因组关联 (GWA) 药物消费行为和基因表达分析。这些分析表明，变体 与药物消耗表型相关的大部分位于非编码基因组区域，并且 据推测，它们通过基因调控发挥其表型效应。我们衍生出基因调控 来自基因表达中自然发生的遗传变异的网络并构建了基因图谱 单细胞分辨率下可卡因暴露后果蝇大脑中的表达变化。挑战 现在的任务是了解变异如何共同作用来影响药物偏好的变化，并确定 使用系统遗传学分析的基础分子网络。这里，我们建议使用1200个新的DGRP 绘制与可卡因偏好相关的自然发生的变异和基因的线，大大增加了 比我们之前的研究更有力量和精确度，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的因果关系 与可卡因偏好和基因调控网络的关联。从这些研究中获得的信息 可以作为后续哺乳动物系统和人类群体转化研究的蓝图 基于基本生物过程的直系学和进化守恒，并扩展 与人类药物敏感性变异相关的遗传框架超出了狭窄的候选范围 迄今为止检查的基因。