From single flies to many genes: Using Drosophila to explore the genetics of psychostimulant consumption.
From single flies to many genes: Using Drosophila to explore the genetics of psychostimulant consumption.
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从单只果蝇到许多基因：利用果蝇探索精神兴奋剂消费的遗传学。
DOI：
10.1073/pnas.2109994118
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发表时间：
2021
影响因子：
11.1
通讯作者：
Rothenfluh,Adrian
中科院分区：
文献类型：
--
作者：
Titos,Iris;Rothenfluh,Adrian
在我们的日常生活中，我们经常接触到成瘾剂，如止痛药，烟草，酒精，甚至食物，性或视频游戏。虽然大多数人不会在接触这些物质后上瘾，但一部分人会。是什么决定了一个人在接触成瘾剂后是否会发展出一种病理模式？家庭研究揭示了药物反应和成瘾的遗传影响，成瘾实际上是最可遗传的精神疾病之一（1）。尽管如此，在人类研究中确定使个体更容易上瘾的特定基因一直是一个挑战。其原因包括由于成瘾的多基因性质而需要大样本量，其中许多基因的影响很小。此外，成瘾还受到许多环境因素的影响，如社会经济地位、童年创伤、药物本身的可用性/流行程度以及首先进行此类大型研究的成本（时间和金钱）。这些限制中的许多可以通过使用模式生物来避免，特别是那些允许高通量测定的生物，如黑腹果蝇。这是贝克等人最近在PNAS上发表的一篇论文。(2)通过测定18，000只果蝇在添加或不添加精神兴奋剂可卡因和甲基苯丙胺的情况下对蔗糖的消耗来解决问题（图1）。当暴露于酒精、可卡因和甲基苯丙胺等滥用物质时，黑腹果蝇表现出与人类相似的行为（3），它们的遗传背景和环境可以被严格控制。大约75%的人类致病基因在果蝇中是保守的（4），支持将苍蝇发现转化为人类的潜力，就像酒精成瘾相关基因一样（5）。在过去100年的大部分时间里，醋蝇一直是遗传模式生物，研究人员用孟德尔遗传方法研究了果蝇，其中一个基因被操纵，并研究了由此产生的表型。在过去的二十年里，Trudy Mackay和Robert Anholt的研究小组一直在开创一种不同的方法：他们不是寻找具有大表型效应的单个基因，而是绘制了许多类似于人类全基因组关联研究（GWAS）的数量性状。这是由他们开发的果蝇遗传参考小组（DGRP）（6）实现的，该小组由1000个野生来源的果蝇品系组成。这些品系中的每一个基因都有两个相同的等位基因，尽管它们之间的所有基因都有不同的等位基因，并且每个品系都在基因组DNA水平上进行了完全测序。DGRP组已接受许多表型调查，随后进行GWAS，以鉴定与目标表型相关的变体（7）。这包括他们自己的研究，在该研究中，他们对46个DGRP品系的可卡因和甲基苯丙胺消费偏好进行了表型分析，并分离出了映射到1，358个基因的2，814个单核苷酸多态性（SNP）（8）AGRP菌株通常在（遗传上相同的）同胞的组中进行测定，因此遗传变异存在于1000个固定菌株和组合中。事实上，每只苍蝇和每个人（尽管偶尔有双胞胎）都是自然发生的遗传SNP变体的独特组合。为了模拟这种更自然的种群遗传结构，Baker et al. (2)创建了一个先进的交叉人口（AIP）研究药物消费。他们从37个高度多样化的DGRP品系中产生了AIP，这些品系随机杂交了50多代，产生了...
In our everyday life, we are often exposed to addictive agents like pain killers, tobacco, alcohol, even food, sex, or video games. Although the majority of people will not develop an addiction upon contact with those agents, a part of the population will. What determines whether a person is going to develop a pathological pattern upon exposure to an addictive agent? Family studies reveal a genetic influence in drug responses and addiction, and addictions are actually one of the most hereditable psychiatric disorders (1). Despite this, it has been challenging to identify specific genes that make an individual more susceptible to becoming addicted in human studies. The reasons for this include the need for large sample sizes due to the polygenic nature of addiction, where many genes have small effects. Furthermore, addiction is influenced by many environmental factors, such as socioeconomic status, childhood trauma, the availability/prevalence of the drug itself, and the cost (in time and money) to perform such large studies in the first place. Many of these limitations can be avoided by the use of model organisms, especially ones that allow for highthroughput assays like Drosophila melanogaster. This is what a recent PNAS paper by Baker et al.(2) tackles by assaying 18,000 single flies for their consumption of sucrose with, or without, the addition of the psychostimulants cocaine and methamphetamine (Fig. 1). Drosophila melanogaster exhibit behaviors similar to humans when exposed to substances of abuse like alcohol, cocaine, and methamphetamine (3), and their genetic background and environment can be tightly controlled. Around 75% of disease-causing genes in humans are conserved in Drosophila (4), supporting the potential to translate fly discoveries to humans, as has been done repeatedly for alcohol addictionrelated genes (5). During much of the past 100 y that vinegar flies have been a genetic model organism, researchers have studied Drosophila with Mendelian genetic approaches, where one gene is manipulated, and the resulting phenotype is studied. For the last two decades, the research group of Trudy Mackay and Robert Anholt has been pioneering a different approach: instead of searching for single genes with large phenotypic effects, they have been mapping many quantitative traits similar to human genomewide association studies (GWASs). This was enabled by their development of the Drosophila Genetic Reference Panel (DGRP)(6), which consists of a population of∼ 200 wild-derived fly lines. Each of these lines has two identical alleles per gene—although with different alleles for all genes between them—and each line is fully sequenced at the genomic DNA level. The DGRP panel has been subjected to many phenotypic surveys followed by GWASs to identify variants that correlate with the phenotypes of interest (7). This has included their own study, where they phenotyped 46 DGRP lines for their cocaine and methamphetamine consumption preference and isolated 2,814 singlenucleotide polymorphisms (SNPs) that mapped to 1,358 genes (8).DGRP strains are generally assayed in groups of (genetically identical) siblings, and thus the genetic variation is present in∼ 200 fixed strains and combinations. In reality, each fly, and each person (the occasional twin notwithstanding), is a unique combination of naturally occurring genetic SNP variants. To simulate this more natural genetic architecture of a population, Baker et al.(2) created an advanced intercross population (AIP) to study drug consumption. They generated the AIP from 37 highly diverse DGRP lines, which were randomly crossbred for over 50 generations, yielding …