Exploratory locomotion, a predictor of addiction vulnerability, is oligogenic in rats selected for this phenotype.
Exploratory locomotion, a predictor of addiction vulnerability, is oligogenic in rats selected for this phenotype.
复制标题
探索性运动是成瘾脆弱性的预测因子，在选择这种表型的大鼠中是寡基因的。
DOI：
10.1073/pnas.1820410116
复制
发表时间：
2019
影响因子：
11.1
通讯作者：
Goldman,David
中科院分区：
文献类型：
--
作者：
Zhou,Zhifeng;Blandino,Peter;Yuan,Qiaoping;Shen,Pei-Hong;Hodgkinson,ColinA;Virkkunen,Matti;Watson,StanleyJ;Akil,Huda;Goldman,David
通过实验选择的模式生物可以揭示它们所模拟的复杂疾病的遗传结构的隐藏特征。成瘾是由不同的中间表型和途径引起的疾病表型，因此可能是高度多基因的。高反应（bHR）和低反应（bLR）大鼠品系已经被选择性地繁殖（B）用于探索性运动（EL），探索性运动是一种与寻求新奇、对奖励的冲动反应和对成瘾的脆弱性相关的行为表型，并且与自发性焦虑和抑郁样行为负相关。对选择的快速反应表明对EL有较大影响的基因座。使用HR和LR大鼠的外显子组测序，我们确定了两个品系之间分离的基因编码区的等位基因。对bHR × bLR杂交F2代大鼠进行数量性状基因座（QTL）分析，证实这些区域含有影响EL的基因。7个全基因组显著QTL的组合效应约占EL总方差的三分之一，遗传因素引起的方差的三分之二，与从F2动物的表型分布和对选择的快速反应估计的EL的寡基因结构一致。人类的遗传关联将APBA 2（最强QTL中心基因的直系同源物）与物质使用障碍和相关行为表型联系在一起。我们的发现也与分子和动物行为学研究一致，这些研究表明Apba 2参与了运动。这些结果为影响EL的基因/位点提供了多层次的证据。他们揭示了人工选择的动物中寡基因的遗传结构，以模拟人类更复杂的疾病。
Artificially selected model organisms can reveal hidden features of the genetic architecture of the complex disorders that they model. Addictions are disease phenotypes caused by different intermediate phenotypes and pathways and thereby are potentially highly polygenic. High responder (bHR) and low responder (bLR) rat lines have been selectively bred (b) for exploratory locomotion (EL), a behavioral phenotype correlated with novelty-seeking, impulsive response to reward, and vulnerability to addiction, and is inversely correlated with spontaneous anxiety and depression-like behaviors. The rapid response to selection indicates loci of large effect for EL. Using exome sequencing of HR and LR rats, we identified alleles in gene-coding regions that segregate between the two lines. Quantitative trait locus (QTL) analysis in F2 rats derived from a bHR × bLR intercross confirmed that these regions harbored genes affecting EL. The combined effects of the seven genome-wide significant QTLs accounted for approximately one-third of the total variance in EL, and two-thirds of the variance attributable to genetic factors, consistent with an oligogenic architecture of EL estimated both from the phenotypic distribution of F2 animals and rapid response to selection. Genetic association in humans linkedAPBA2, the ortholog of the gene at the center of the strongest QTL, with substance use disorders and related behavioral phenotypes. Our finding is also convergent with molecular and animal behavioral studies implicating Apba2 in locomotion. These results provide multilevel evidence for genes/loci influencing EL. They shed light on the genetic architecture of oligogenicity in animals artificially selected for a phenotype modeling a more complex disorder in humans.