Nicotine consumption QTL: Fine mapping, selective breeding and sequencing

尼古丁消耗QTL：精细定位、选育和测序

基本信息

批准号：
9328056
负责人：
RICHARD A RADCLIFFE
金额：
$ 27.42万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2018-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Genetics clearly contributes to individual risk for nicotine dependence in humans and variations in nicotine sensitivity in experimental animals. In mice, several behavioral and physiological responses to nicotine have been demonstrated to be influenced by genetics. However, none of the specific genes that contribute to the genetic influence on nicotine sensitivity in mice have been identified. These genes remain an untapped source of information that almost certainly will improve our understanding of what drives individual differences in nicotine sensitivity. For example, the recent discovery that variants in human CHRNA5 are associated with risk for nicotine dependence in humans led to follow-up studies in rodents which not only helped to identify a specific neuronal pathway critical for controlling the level of nicotine consumption, but also demonstrated that this gene impacts individual differences in nicotine self-administration not by increased sensitivity to the reinforcng effects of nicotine at low doses but rather a lack of the loss of reinforcement at aversive doses. This is just one of many examples where the identification of a gene that contributes to individual variability in a phenotypic measure can lead to significant insights into the underlying biology of the measure. We previously have mapped chromosomal regions that harbor genes or genes that contribute to individual differences in oral nicotine intake in mice and it is the goal f this project to follow up this initial finding to identify the genes that contribute to variation i nicotine intake. For this, we will again map chromosomal regions that impact nicotine intake but this time in a panel of mice that will allow us to define with much greater precision the regions i the genome that harbor genes that impact nicotine intake. We will follow this up with selective breeding to produce lines of mice that differ in nicotine intake. The selection process should produce mouse lines that are enriched for alleles that are involved in increasing or decreasing nicotine intake. Finally, we will perform whole genome sequencing on the selected lines. We will use these sequencing data to establish whether the chromosomal regions identified through mapping are enriched through the selection process and to identify all variants within the region. We also will analyze the sequence data for other potential chromosomal regions that have been enriched through selection for nicotine consumption. This multi-tiered approach should allow us to substantially narrow the search for variants that influence nicotine intake and potentially lead to the identification of causal variants (functional variants that contribute to individual variabiity in nicotine consumption).

描述（由适用提供）：遗传学显然有助于人类对尼古丁依赖性的个人风险，以及实验动物中尼古丁敏感性的变化。在小鼠中，已经证明对尼古丁的几种行为和身体反应受到遗传学的影响。但是，尚未确定有助于对小鼠尼古丁敏感性的遗传影响的特定基因。这些基因仍然是未开发的信息来源，几乎可以肯定会提高我们对驱动尼古丁敏感性个体差异的原因的理解。例如，最近发现，人类ChRNA5中的变异与人类尼古丁依赖性的风险有关，导致了对啮齿动物的后续研究，这不仅有助于确定一种特定的神经元途径，这对于控制尼古丁消耗的水平而言，这一特定的神经元途径至关重要，而且还表明，这种基因在尼古丁的差异中不影响尼古丁自我的损失，而在NIC上造成了良好的效果，而不是促进NIC效应的疾病，而对NIC的造成了良好的影响，而NIC的损失效果会增加NIC的效果，而NIC的效应是造成NIC效应的效果。厌恶剂量的加固。这只是众多示例之一，在表型措施中有助于个人变异性的基因的识别可以导致对基础的重要见解测量的生物学。我们以前已经绘制了染色体区域，该染色体区域含有基因或基因，这些基因或基因导致小鼠口服尼古丁摄入的个体差异，而该项目的目标是遵循此初步发现以识别导致变异I尼古丁摄入的基因。为此，我们将再次绘制影响尼古丁摄入量的染色体区域，但这次是在一组小鼠中，这将使我们能够更加精确地定义影响尼古丁摄入的基因组的区域I。我们将通过选择性育种来跟进这一点，以产生尼古丁摄入量不同的小鼠。选择过程应产生小鼠线，这些小鼠线富含与增加或减少尼古丁摄入有关的等位基因。最后，我们将在选定的线上执行整个基因组测序。我们将使用这些测序数据来确定是否通过映射识别的染色体区域是否通过选择过程丰富并识别区域内的所有变体。我们还将分析其他潜在染色体区域的序列数据，这些染色体区域已通过选择尼古丁消耗而丰富。这种多层方法应该使我们可以实质上缩小搜索影响尼古丁摄入量并潜在领导的变体的搜索鉴定因果变异（有助于尼古丁消耗中个体变异的功能变体）。