Buck K J, Hood H M
Department of Behavioral Neuroscience and Portland Alcohol Research Center, Oregon Health Sciences University, and Department of Veterans Affairs Medical Center, R&D40, 3710 SW US Veterans Hospital Road, Portland, Oregon 97201, USA.
Mamm Genome. 1998 Dec;9(12):975-8. doi: 10.1007/s003359900909.
The ultimate goal of quantitative trait locus (QTL) mapping is to identify the genes affecting complex traits. Using animal models, we recently identified QTLs on mouse Chromosomes (Chrs) 1, 4, and 11 affecting genetic predisposition to acute alcohol withdrawal. Among mice derived from the C57BL/6J (B6) and DBA/2J (D2) inbred strains, the locus identified on Chr 11 ( approximately 20 cM) accounted for 12% of the genetic variability in withdrawal liability. Candidate genes in proximity to this QTL encode the gamma2, alpha1, and alpha6 subunits of GABAA receptors. The present studies identify a polymorphism between the B6 and D2 strains in the gamma2 subunit gene, Gabrg2, and expand genotypic analysis to their BXD recombinant inbred strains. This polymorphism predicts a difference in amino acid sequence (Ala-11 vs. Thr-11) within the extracellular amino-terminal region of the gamma2 subunit. Analysis using BXD strain means for acute alcohol withdrawal severity suggests that the gamma2 subunit polymorphism is genetically correlated with alcohol withdrawal severity. This is the first report that QTL mapping for an alcohol-related trait has successfully led to the identification of a polymorphic candidate gene product that is genetically associated with the trait.
数量性状基因座（QTL）定位的最终目标是识别影响复杂性状的基因。利用动物模型，我们最近在小鼠1号、4号和11号染色体（Chrs）上鉴定出了影响急性酒精戒断遗传易感性的QTL。在源自C57BL/6J（B6）和DBA/2J（D2）近交系的小鼠中，在11号染色体上鉴定出的基因座（约20厘摩）占戒断易感性遗传变异的12%。该QTL附近的候选基因编码GABAA受体的γ2、α1和α6亚基。本研究鉴定出了γ2亚基基因Gabrg2中B6和D2品系之间的一个多态性，并将基因型分析扩展到它们的BXD重组近交系。这种多态性预测了γ2亚基细胞外氨基末端区域内氨基酸序列的差异（丙氨酸-11与苏氨酸-11）。使用BXD品系急性酒精戒断严重程度的均值进行分析表明，γ2亚基多态性与酒精戒断严重程度存在遗传相关性。这是第一份关于酒精相关性状的QTL定位成功导致鉴定出与该性状存在遗传关联的多态性候选基因产物的报告。
