Gill K, Desaulniers N, Desjardins P, Lake K
Montreal General Hospital Research Institute and Psychiatry Department, McGill University, Addictions Unit, 1604 Pine Avenue West, Montreal, Quebec, Canada H3G 1B4.
Mamm Genome. 1998 Dec;9(12):929-35. doi: 10.1007/s003359900902.
The purpose of the present study was to characterize the C57BL/6J, A/J, and AXB/BXA Recombinant Inbred (RI) strains of mice for voluntary alcohol consumption. Quantitative Trait Locus (QTL) analysis was used to provide provisional location of QTLs for alcohol consumption. The inbred strains were screened for levels of alcohol intake (calculated as alcohol preference and absolute alcohol consumption) by receiving 4 days of forced exposure to a 10% (wt/vol) solution of alcohol, followed by 3 weeks of free choice between water and 10% alcohol. A wide and continuous distribution of values for alcohol consumption and preference was obtained in the AXB/BXA RI strains, confirming polygenic influences on alcohol-related behaviors. Significant gender differences were found for both alcohol preference [F28,651 = 2.12, p < 0.001] and absolute alcohol consumption [F28,647 = 2.57, p < 0.001]. In males, putative QTLs were mapped to chromosomes (Chrs) 2, 5, 7, 10, 11, and 16. Multiple regression analysis indicated that approximately 75% of the genetic variance in alcohol preference in males could be accounted for by three of the QTL regions. Several of the putative QTLs appeared to be male-specific (Tyr on Chr 7; D10Mit126 on Chr 10; D11Mit61 on Chr 11). In females, seven putative QTLs were mapped to Chrs 2, 4, 5, 7, 11, 16, and 19. Approximately 90% of the genetic variance in alcohol preference in females could be accounted for by four QTL regions, as determined by multiple regression. The QTL on Chr 11 near D11Mit35 appeared to be female-specific. This site was close to a female-specific QTL (Alcp2) previously mapped in C57BL/6J x DBA/2J backcrosses by Melo and coworkers (Nat Genet 13, 147, 1996). The QTLs mapped for alcohol preference in the present study must be considered suggestive at the present time, since only D2Mit74 met very strict statistical criteria for significance. However, the concordance across several studies for the loci on Chrs 2, 4, 7, 9, and 11 suggest that some common QTLs influencing alcohol preference have been identified. Confirmation of QTLs mapped in the present study is currently being conducted in a new series of recombinant congenic (RC) strains developed from reciprocal backcrosses between the A/J and C57BL/6J progenitors. The concomitant use of both RI and RC strains developed from the same progenitors should provide a powerful means of detecting, confirming, and mapping QTLs for alcohol-related traits.
本研究的目的是对C57BL/6J、A/J和AXB/BXA重组近交（RI）系小鼠的自愿酒精摄入量进行特征描述。采用数量性状基因座（QTL）分析来确定酒精摄入量QTL的初步定位。通过让近交系小鼠连续4天强制接触10%（重量/体积）酒精溶液，随后3周在水和10%酒精之间自由选择，来筛选酒精摄入量水平（以酒精偏好和绝对酒精消耗量计算）。在AXB/BXA RI系小鼠中获得了广泛且连续的酒精消耗量和偏好值分布，证实了多基因对酒精相关行为的影响。在酒精偏好[F28,651 = 2.12，p < 0.001]和绝对酒精消耗量[F28,647 = 2.57，p < 0.001]方面均发现了显著的性别差异。在雄性小鼠中，推测的QTL被定位到染色体（Chrs）2、5、7、10、11和16上。多元回归分析表明，雄性小鼠酒精偏好中约75%的遗传变异可由三个QTL区域解释。几个推测的QTL似乎是雄性特异性的（位于Chr 7上的Tyr；位于Chr 10上的D10Mit126；位于Chr 11上的D11Mit61）。在雌性小鼠中，七个推测的QTL被定位到Chrs 2、4、5、7、11、16和19上。多元回归分析确定，雌性小鼠酒精偏好中约90%的遗传变异可由四个QTL区域解释。位于Chr 11上靠近D11Mit35的QTL似乎是雌性特异性的。该位点靠近Melo及其同事先前在C57BL/6J×DBA/2J回交中定位的一个雌性特异性QTL（Alcp2）（《自然遗传学》13卷，第147页，1996年）。由于目前只有D2Mit74符合非常严格的显著性统计标准，因此本研究中定位到的酒精偏好QTL目前只能被视为提示性的。然而，多项研究中Chrs 2、4、7、9和11上的位点一致性表明，已经鉴定出一些影响酒精偏好的常见QTL。目前正在利用A/J和C57BL/6J祖代之间的相互回交产生的一系列新的重组同类系（RC）小鼠对本研究中定位的QTL进行验证。同时使用源自相同祖代的RI系和RC系小鼠应该为检测、确认和定位酒精相关性状的QTL提供一种强大的方法。
