School of Biological and Chemical Sciences, Queen Mary, University of London, London, United Kingdom.
School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, United Kingdom.
Elife. 2020 Mar 25;9:e51295. doi: 10.7554/eLife.51295.
To facilitate smoking genetics research we determined whether a screen of mutagenized zebrafish for nicotine preference could predict loci affecting smoking behaviour. From 30 screened F sibling groups, where each was derived from an individual ethyl-nitrosurea mutagenized F fish, two showed increased or decreased nicotine preference. Out of 25 inactivating mutations carried by the F fish, one in the gene segregated with increased nicotine preference in heterozygous individuals. Focussed SNP analysis of the human locus in cohorts from UK (n=863) and Finland (n=1715) identified two variants associated with cigarette consumption and likelihood of cessation. Characterisation of mutant larvae and adult fish revealed decreased sensitivity to the dopaminergic and serotonergic antagonist amisulpride, known to affect startle reflex that is correlated with addiction in humans, and increased mRNA expression in mutant larvae. No effect on neuronal pathfinding was detected. These findings reveal a role for SLIT3 in development of pathways affecting responses to nicotine in zebrafish and smoking in humans.
为了促进吸烟遗传学研究，我们确定对尼古丁偏好进行诱变斑马鱼筛选是否可以预测影响吸烟行为的基因座。从 30 个筛选的 F 同胞群体中，每个群体均来自单个乙基亚硝脲诱变的 F 鱼，其中两个群体表现出增加或减少尼古丁偏好。在 F 鱼携带的 25 个失活突变中，一个位于 基因与杂合个体中尼古丁偏好增加相关。在来自英国（n=863）和芬兰（n=1715）的队列中，对人类 基因座的重点 SNP 分析确定了两个与吸烟量和戒烟可能性相关的变体。对突变幼虫和成年鱼的特性分析显示，对多巴胺能和血清素拮抗剂阿米舒必利的敏感性降低，已知该拮抗剂会影响与人类成瘾相关的惊吓反射，并且突变幼虫中的 mRNA 表达增加。未检测到对神经元轨迹的影响。这些发现揭示了 SLIT3 在影响斑马鱼对尼古丁反应和人类吸烟的途径发育中的作用。
